Azapurinones

ABSTRACT

8-AZAPURIN-6-ONES SUBSTITUTED IN THE 2-POSITION BY AN UNSUBBSTITUTED OR SUBSTITUTED PHENYL OR NAPHTHYL GROUP, OR BY AN ALKENYL OR ALKYNYL GROUP, A CYCLOALKYL GROUP,  NA ALKYL GROUP CONTAINING 2 TO 10 CARBON ATOMS CARRYING ONE OR GROUP CONTAINING 1 TO 10 CARBO ATOMS, OR AN ALKYL MORE SUNSTITUTENTS SELECTED FROM HALOGEN ATOMS AND HYDROXY, CYCLOALKYL, ALDOXY, PHENYL AND SUBSTITUTED PHENYL GROUPS, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF POSSESS PHARMACOLOGICAL PROPERTIES USEFUL, FOR EXAMPLE, IN THE TREATMENT OF ALLERGIC BRONCHIAL ASTHMA.

United States Patent 015cc 3,819,631 AZAPURINONES Barbara JoyceBroughton, Croydon, Bryan John Large, Upminster, Stuart MalcolmMarshall, Stanford-le-Hope, David Lord Pain, Upminster, and KennethRobert Harry Wooldridge, Brentwood, England, assignors to May & BakerLimited, Dagenaham, Essex, England No Drawing. Filed Dec. 14, 1971, Ser.No. 207,986 Claims priority, application Great Britain, Dec. 15, 1970,59,552/70, 59,556/70; Oct. 26, 1971, 49,756/71; Nov. 17, 1971, 53,457/71Int. Cl. C07d 51/46 US. Cl. 260-2564 F 6 Claims ABSTRACT OF THEDISCLOSURE 8-Azapurin-6-ones substituted in the 2-position by anunsubstituted or substituted phenyl or naphthyl group, or by an alkenylor alkynyl group, a cycloalkyl group, an alkyl group containing 2 to 10carbon atoms, or an alkyl group containing 1 to 10 carbon atoms carryingone or more substituents selected from halogen atoms and hydroxy,cycloalkyl, alkoxy, phenyl and substituted phenyl groups, andpharmaceutically acceptable salts thereof, possess pharmacologicalproperties useful, for example, in the treatment of allergic bronchialasthma.

This invention relates to new therapeutically useful 8- azapurin-6-onederivatives, to processes for their preparation and to pharmaceuticalcompositions containing them.

As a result of research and experimentation, it has been found that thenew 8-azapurin-6one derivatives represented by the general formula:

H N HN165\ I SN 2 4 [wherein R represents a phenyl or naphthyl group,which may optionally carry one or more (preferably at most three)substituents selected from halogen (preferably fluorine, chlorine orbromine) atoms and hydroxy, alkyl, phenylalkyl, alkoxy, alkenyloxy,alkynyloxy, alkoxyalkoxy, phenoxy, aralkoxy (e.g. phenylalkoxy),alkylthio, hydroxyalkyl, nitro, alkanesulphonyl, alkanoyl,alkoxycarbonyl, amino, trifluoromethyl and methylenedioxy groups andamino groups substituted by one or two groups selected from alkyl,phenyl, alkanoyl, alkanesulphonyl and arenesulphonyl (e.g.benzenesulphonyl) groups, or R represents a straightor branched-chainalkenyl or alkynyl group containing from 2 to 6 carbon atoms, acycloalkyl group containing from 3 to 8 carbon atoms (e.g. cyclohexyl),a straightor branched-chain alkyl group containing from 2 to 10 carbonatoms (preferably isopropyl, butyl or isobutyl), or a straightorbranched-chain alkyl group containing from 1 to 10 carbon atoms(preferably methyl or ethyl) carrying one or more (preferably at mosttwo) substituents selected from halogen atoms, hydroxy groups,cycloalkyl groups containing from 3 to 8 carbon atoms (preferablycyclohexyl), straightor branched-chain alkoxy groups containing from 1to 6 carbon atoms, and phenyl groups optionally carrying one or more(preferably at most two) substituents selected from halogen atoms andstraightor branched-chain alkyl and alkoxy groups containing from 1 to 6carbon atoms, hydroxy groups, and phenylalkoxy (e.g. benzyloxy) groupsin which the alkoxy moiety contains 1 to 6 carbon atoms] andpharmaceutically accept- 3,819,631 Patented June 25, 1974 able saltsthereof, possess valuable pharmacological properties.

In this Specification, when R represents a substituted phenyl orsubstituted naphthyl group, alkyl groups and alkyl portions ofphenylalkyl, alkylthio, aralkoxy, alkanoyl, alkanesulphonyl,hydroxyalkyl and alkoxycarbonyl substituents contain from 1 to 6 carbonatoms; each alkyl portion of an alkoxyalkoxy substituent contains from 1to 6 carbon atoms; alkoxy substituents contain from 1 to 10 carbonatoms; alkenyloxy and alkynyloxy substituents contain 2 to 10 carbonatoms and alkyl and alkanoyl groups on amino substituents, and alkaneportions of alkanesulphonyl groups on amino substituents, contain from 1to 6 carbon atoms; phenoxy substituents, and phenyl groups on aminosubstituents, may carry one or more substituents selected from halogen(e.g. fluorine, chlorine or bromine) atoms, and alkyl and alkoxy groupscontaining from 1 to 6 carbon atoms; aryl (e.g. phenyl) portions ofaralkoxy substituents may carry one or more substituents selected fromhalogen (e.g. fluorine, chlorine or bromine) atoms, alkyl and alkoxygroups containing from 1 to 6 carbon atoms and nitro groups; and arene(e.g. benzene) portions of arenesulphonyl groups on amino substituentsmay carry one or more alkyl groups containing from 1 to 6 carbon atoms(e.g. methyl). The carbon atoms in the alkyl, alkoxy, alkanoyl, alkane,alkenyloxy and alkynyloxy groups or moieties may be in straightorbranched-chain.

It will be understood by those skilled in the art that the compounds offormula I exhibit tautomerism such that each of the hydrogen atomsdepicted as residing on the nitrogen atoms in the 1- and 9-positions mayreside on any of the nitrogen atoms in the 1-, 3-, 7-, 8- and 9-positions or on the oxygen atom connected to the carbon atom in the6-position, and that all the forms thus described may be present to agreater or lesser degree and are in a state of dynamic equilibrium witheach other. Furthermore, in certain cases the substituent R contributesto optical and/or stereoisomerism. All such forms are embraced by thepresent invention.

The present invention includes pharmaceutically acceptable salts ofcompounds of formula I with pharmaceutically acceptable bases. By theterm pharmaceutically acceptable salts is meant salts the cations ofwhich are relatively innocuous to the animal organism when used intherapeutic doses so that the beneficial pharmacological properties ofthe parent compounds of general formula I are not vitiated by sideeffects ascribable to those cations. Suitable salts include the alkalimetal, e.g. sodium and potassium, and ammonium salts and salts of aminesknown in the art to be pharmaceutically acceptable, e.g. ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine,diethylamine, triethylamine, 2- amino-2-(hydroxymethyl)propane-1,3-dioland 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

Pharmaceutically acceptable salts may be prepared by the reactiontogether of stoichiometric quantities of a compound of formula I and theappropriate base, that is to say, a base as described immediatelyhereinbefore, for example at an elevated temperature, with or without anappropriate solvent, preferably followed by recrystallization from anappropriate solvent, for example a hydroxylic solvent, e.g. water, ofthe salt so formed.

According to a feature of the present invention, compounds of formula Iare prepared from compounds of the general formula:

EN l NH:

(wherein R is as hereinbefore defined) by the action of a source ofnitrous acid, for example a nitrite of an alkali metal, e.g. sodiumnitrite or potassium nitrite, together with an acid, for example diluteaqueous hydrochloric acid, preferably as the reaction medium, at atemperature near or below the ambient temperature, for example betweenand 30 C.

Compounds of formula II may be prepared, for example, by the reductionof compounds of the general formula:

III

(wherein R is as hereinbefore defined) with suitable reducing agents,for example sodium dithionite in water or an aqueous lower alkanol, e.g.aqueous ethanol, optionally in the presence of a base, e.g.triethylamine.

Compounds of formula II may also be prepared by the reduction ofcompounds of the general formula:

(wherein R is as hereinbefore defined, X represents the anion of asuitable acid, for example an inorganic acid, (e.g. hydrochloric acid),or a strong organic acid (e.g. methanesulphonic or toluenep-sulphonicacid), and n is the basicity of that acid) with an alkyla-oximinocyanoacetate, for example ethyl a-oximinocyanoacetate, in thepresence of a lower alkoxide of an alkali metal in a lower alkanol, forexample sodium ethoxide in ethanol, preferably at an elevatedtemperature, advantageously at the reflux temperature of the reactionmixture.

Compounds of formula III may also be prepared by the nitrosation ofcompounds of the general formula:

VII

(wherein Ar is as hereinbefore defined, and R represents an alkyl groupcontaining from 1 to 6 carbon atoms, preferably methyl or ethyl) in thepresence of a lower alkoxide of an alkali metal in a lower alkanol, forexample sodium ethoxide in ethanol, preferably at an elevatedtemperature, advantageously at the reflux temperature of the reactionmixture.

Compounds of formula IV may alternatively be prepared by the reaction ofalkaline aqueous solutions of compounds of formula VI with solutions ofcompounds of the general formula:

(wherein Ar, X and n are as hereinbefore defined) in water or a diluteacid of the formula H X (wherein X and n are as hereinbefore defined),preferably at below room temperature, for example at 010 C.

Compounds of formula V may be prepared by the action of acids of thegeneral formula H,,X (wherein X and n are as hereinbefore defined) oncompounds of the general formula:

VIII

NH: IX

(wherein R is as hereinbefore defined), which may themselves beprepared, for example, by the catalytic hydrogenation of compounds ofthe general formula:

NHOH

(wherein R is as hereinbefore defined), preferably using Raney nickel ascatalyst.

Compounds of formula X may be prepared by the reaction of hydroxylaminehydrochloride with compounds of the general formula:

RCN XI (wherein R is as hereinbefore defined) with a basic catalyst in asuitable solvent, for example sodium carbonate in aqueous ethanol,sodium hydride in ethyl cellosolve, 0r triethylamine, which may also actas solvent.

Compounds of formula IX may also be prepared by the reaction ofalcoholic ammonia with compounds of the general formula:

(wherein R and R are as hereinbefore defined and Y- represents asuitable anion, for example a chloride, borofluoride or fluorosulphonateion) at temperatures between, for example 0 and 60 C.

Compounds of formula IX, wherein R is other than a substituted orunsubstituted phenyl or naphthyl group, may also be prepared by thereaction of a compound M+NH where M represents a sodium or potassiumatom, with compounds of formula XI according to the method described byJ. Newbery and W. Webster, J. Chem. Soc., 1947, 738.

Compounds of formula XII, wherein R and R are as hereinbefore defined(but preferably not a phenyl group with a substituent in the 2- or6-position, nor a naphth-lyl group, nor a naphth-Z-yl group with asubstituent in the lor 3-position) and Y- is a chloride ion, may beprepared by the action of an anhydrous solution of hydrogen chloride inthe corresponding alkanol for formula R OH on compounds of formula XI(wherein R is as hereinbefore defined).

Compounds of formula XII, wherein R and R are as hereinbefore definedand Y- is a borofluoride or a fluorosulphonate ion, may be prepared bythe reaction of the appropriate trialkyloxonium borofluoride and alkylfluoro- XII sulphonate respectively [wherein the alkyl group(s) aregroups R with compounds of the general formula:

RCONH XIII (wherein R is as hereinbefore defined) in a suitable solvent,for example anhydrous methylene chloride, preferably at or near theambient temperature.

Compounds of formula VI may be prepared, for example, by the reaction ofcompounds of formula V with an alkyl cyanoacetate, for example ethylcyanoacetate, in the presence of a lower alkoxide of an alkali metal ina lower alkanol, for example sodium ethoxide in ethanol, preferably atan elevated temperature, advantageously at the refiux temperature of thereaction mixture.

According to a further feature of the present invention, compounds offormula I are prepared by the reaction of compounds of the generalformula:

(wherein R, X and n are as hereinbefore defined, and R and R eachrepresent a hydrogen atom or an alkyl group containing from 1 to 6carbon atoms, preferaby methyl) with compounds of the general formula:

N/ XV (wherein R represents a hydroxy, alkoxy, amino, alkylamino ordialkylamino group, the alkoxy group and the alkyl groups in the saidalkylamino and dialkylamino groups each containing from 1 to 6 carbonatoms) at elevated temperatures, preferably at 150 C. to 250 C., in thepresence of a base, preferably sodium acetate, and advantageously in thepresence of a suitable solvent, for example polyethylene glycol 200, ina manner similar to that described by B. R. Baker and J. A. Kozma, J.Med. Chem., 1968, 11, 656.

Compounds of formula XIV may be prepared by the action of the compoundsof general formula H X (wherein X and n are as hereinbefore defined) oncompounds of the general formula:

(wherein R, R and R are as hereinbefore defined), which may themselvesbe prepared by the reaction of compounds of the general formula:

NHR R XVII (wherein R and R are as hereinbefore defined) with compoundsof formula XII at temperatures between, for example, and 60 C. andadvantageously in the presence of a suitable organic solvent, preferablya lower alkanol, e.g. ethanol.

The compounds of formula XV wherein R represents an amino group (i.e..5-amino-4-carbamoyl-1H-1,2,3-triazole), or a hydroxy or alkoxy group,may be prepared by the methods described by J. R. E. Hoover and A. R.Day, J. Amer. Chem. Soc., 1956, 78, 5832, and A. Albert, J. Chem. Soc.,1969 (C), 2076 respectively.

The compounds of formula XV wherein R represents an alkylamino ordialkylamino group may be prepared, for example, from compounds offormula XV, wherein R represents an alkoxy group, by reaction with theappropriate amine, preferably in the presence of a base, e.g. sodiumethoxide in ethanol, or alternatively by debenzylation of compounds offormula XXI depicted hereafter (wherein R represents an alkylamino ordialkylamino group and R" represents a benzyl group), for example bymeans of sodium in liquid ammonia.

According to a further feature of the present invention, compounds offormula I, wherein that carbon atom of the group R by which the saidgroup R is attached to the 2-position of the azapurinone ring bears nohydrogen atoms, such a group R being represented by the symbol R areprepared by the reaction of compounds of the general formula:

R --CZ XVIII (wherein R is as hereinbefore defined and Z is a halogenatom, preferably a chlorine atom) with 5-amino-4carbamoyl-1H-1,2,3-triazole at elevated temperatures, preferably between50 and 150 C. and in the presence of a base, for example potassiumtert-butoxide, and a suitable solvent, for example anhydroustert-butanol.

According to yet a further feature of the present invention, compoundsof formula I are prepared by the reaction of compounds of formula XVwith compounds of formula XII at elevated temperatures, preferablybetween 50 and 200 C., in a suitable solvent, for example anhydrousethanol or anhydrous dimethylformamide, optionally in the presence of asuitable base, for example sodium ethoxide.

According to another feature of the present invention, compounds offormula I (wherein R is a group R as hereinbefore defined) are preparedby the reaction of compounds of the general formula:

(wherein R and R are as hereinbefore defined) with S-amino 4carbamoyl-1H-1,2,3-triazole at an elevated temperature, preferably at C.to 200 C. in an anhydrous inert organic solvent, for example an aromatichydrocarbon (e.g. xylene) and in the presence of an acid (e.g.toluene-p-sulphonic acid) or a Lewis acid (e.g. boron trifluoride)Compounds of formula XIX may be prepared by the method described by L.C. Rinzema, J. Stoffelsma and J. F. Arens, Rec. Trav. Chim., 1959, 78,354.

According to a further feature of the present invention, compounds offormula I are prepared from compounds of the general formula:

u N W x A (wherein R is as hereinbefore defined, and R is a groupheretofore used or described in the literature for the protection ofnitrogen atom constituents of heterocyclic rings, for example a benzyl,toluene-p-sulphonyl or phenacylsulphonyl group, or such a groupsubstituted by, for example, one or more alkyl groups containing from 1to 6 carbon atoms) by known methods for the replacement of suchprotecting groups R by a hydrogen atom. Preferably R represents a benzylgroup, which is replaced by a hydrogen atom, thus preparing compounds offormula I from the corresponding compounds of formula XX, for example bymeans of concentrated aqueous hydrobromic acid at elevated temperatures,by means of sodium in liquid ammonia, or otherwise by hydrogenation inthe presence of a hydrogenation catalyst, for example palladium on charcoal, and in the presence of a strong acid, for exampletrifluoromethanesulphonic acid.

Compounds of formula XX may be prepared, for example, by the reaction ofcompounds of the general formula:

N\N l.

R CO 2N XXI (herein R and R are as hereinbefore defined) with compoundsof formula XIV under similar conditions to those herein-before describedfor the preparation of compounds of formula I by the reaction ofcompounds of formula XV with compounds of formula X IV.

Compounds of formula XXI may be prepared by the methods described by I.R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956 78, 5832, and A.Albert, J. Chem. Soc., 1969 (C), 2379.

Compounds of formula XX, wherein R represents a group R as hereinbeforedefined, may also be prepared by the reaction of compounds of thegeneral formula:

HzNCO N 7 XXII (wherein R is as hereinbefore defined) with compounds offormula XIX under similar conditions to those hereinbefore described forthe preparation of compounds of formula I by the reaction of5-amino-4-carbamoyl-1H- 1,2,3-triazole with compounds of formula XIX.

Compounds of formula XXII may be prepared by methods similar to thosedescribed by J. R. E. Hoover and A. R. Day (op. cit.)

Compounds of formula XX (wherein R is as hereinbefore defined and Rrepresents a group R as hereinbefore defined) may also be made by thereaction of compounds of formula XXII with compounds of formula XVI-IIat elevated temperatures, preferably between 50 and 150 C., and in thepresence of a base, for example potassium tert-butoxide, and a suitablesolvent, for example anhydrous tert-butanol.

Compounds of formula XX may also be prepared by the reaction ofcompounds of the general formula:

RCOZ XXIII HzNC O N HCONH N 1 XXIV (wherein R' is as hereinbeforedefined), preferably at 30 C., in the presence of a base, for examplesodium hydroxide, and in a suitable solvent, for example water, followedby cyclisation of the resulting acylated product by heating to atemperature preferably between 50 and 150 C., in the presence of an acidor preferably in the presence of a base, for example the hydroxide,carbonate or bicarbonate of sodium or potassium, in a suitable solvent,for example aqueous ethanol of water, or an alkoxide (preferably themethoxide or ethoxide) of sodium or potassium in a dry alkanol(preferably methanol or ethanol).

Compounds of formula XXIV may be prepared by the method described by A.Albert, J. Chem. Soc., 1969 (C), 152.

Compounds of formula XX may also be prepared by the reaction ofcompounds of formula XXI with compounds of general formula XII atelevated temperatures, preferably between 50 and 200 C., in a suitablesolvent, for example anhydrous ethanol, optionally in the presence of asuitable base, for example sodium ethoxide.

According to a further feature of the present invention, compounds offormula I are prepared by the reaction of amino 4 carbamoyl 1H 1,2,3triazole with xxv (wherein R is as hereinbefore defined) by the actionof a source of nitrous acid, for example a nitrite of an alkali metal,e.g. sodium nitrite or potassium nitrite, together with an acid, forexample dilute aqueous hydrochloric acid, preferably as the reactionmedium, at an elevated temperature, preferably between 60 and C.

Compounds of formula XXV may be prepared, for example, from compounds ofthe general formula:

N xxvr (wherein R is as hereinbefore defined) by the reaction of asource of nitrous acid, for example a nitrite of an alkali metal, e.g.sodium nitrite or potassium nitrite, together with an acid, for exampledilute aqueous hydrochloric acid, preferably as the reaction medium, ata temperature near or below the ambient temperature, for example between0 and 30 C.

Compounds of formula XXVI may be prepared by the application oradaptation of known methods, for example by the method of J. Weinstock,R. Y. Dunoff and J. G. Williams, J. Medicin. Chem., 1968, 11, 542.

It will be readily appreciated by those skilled in the art thatinterconversions between different compounds of formula I are possible,for example:

(a) compounds of formula I wherein R represents a substituted orunsubstituted phenyl or naphthyl group may be converted to correspondingnitrophenyl or nitronaphthyl compounds of formula I by the applicationof methods known per se for the nitration of phenyl and naphthylmoieties,

(b) nitro-compounds of formula I as formed in (a) may be converted tothe corresponding amino compounds by reduction, for example by catalytichydrogenation using, for example, a platinum oxide-charcoal catalyst,

(c) compounds of formula I wherein R represents a substituted orunsubstituted benzyloxyphenyl group may be converted to thecorresponding hydroxy-phenyl compounds of formula I by reduction, forexample by catalytic hydrogenation using, for example, apalladiumcharcoal catalyst.

By the terms known methods and methds known per se as used in thisSpecification is meant methods heretofore employed or described in theliterature.

The 8-azapurin-6-ones of the present invention possess valuablepharmacological properties, in particular properties of value in thetreatment of respiratory disorders manifested by the interaction oftissue-fixed antibodies with specific antigens, such as allergicbronchial asthma.

In pharmacological tests the new compounds suppress the passivecutaneous anaphylactic (PCA) reaction resulting from combination oftissue-fixed reaginic antibodies with the appropriate antigenic material(termed reagin-allergen combination) and carried out in an essentiallysimilar manner to that described by Ogilvie [Nature (Lond.) (1964), 204,91-92; Immunology, (1967), 12, 112-131]. In the method used to testthese compounds sera were obtained from rats which had been infectedwith larvae of the nematode parasite Nippostrongylus brasiliensis; as aresult of the parasitic infestation reaginic antibodies are elaboratedin the host mammal and are found in sera removed from such animals.Other, noninfected, rats received intradermal injections of appropriatedilutions of such sera and were then given the allergenic material alongwith Evans blue dye intravenously forty-eight hours later.

The allergenic material consisted of supernatant fluid aftercentrifugation of homogenates of adult Nippostrongylus brasiliensisworms which had been maccrated in Tyrodes solution. The sites of PCAreactions were visualised by the effusion of Evans blue dye from thecirculation into those areas as a result of increased capillarypermeability caused by the release of biologicallyactive substances fromcells where reagin-allergen combination had occurred. The new compoundswhen given intravenously to the rats just before injection of allergen,at doses of, for example, 0.01-20 mg./kg., or administered orallyfifteen or forty-five minutes before intravenous injection of allergenat doses of, for example, 0.5200 mg./kg. were able to prevent thedevelopment of the reaction.

In biochemical tests the new compounds inhibit the hydrolysis ofadenosine cyclic 3,5'-monophosphate (cyclic AMP) to adenosine-monophosphate by human lung microsomal cyclic nucleotidephosphodiesterase. In a test carried out in an essentially similarmanner to that described by G. Brooker, L. J. Thomas and M. M. Appleman,Biochemistry, 1968, 7 (12), 4177, the H-adenosine 5-monophosphateobtained, by the action of microsomes of human lung tissue, fromH-cyclic AMP was converted to H-adenosine and phosphate by means of5-nucleotidase. Dowex 2-X8 anion exchange resin was used to adsorbunchanged H-cyclic AMP, thus terminating the enzyme reaction, and theH-adenosine in solution was measured by means of radioactivescintillation counting.

In the method used, a mixture (0.20 ml.) consisting of microsomesprepared from macroscopically normal human lung tissue obtained fromsurgical operations, H- cyclic AMP M), magnesium sulphate (5 mM.), 5-nucleotidase (0.1 mg.) and a new compound of the present invention,contained in a trishhydroxymethylmethylammonium hydrochloride buffer(0.1 M, pH 7.5), was incubated for minutes at 37 C. The enzyme reactionwas then terminated by the addition of Dowex 2-X8 anion exchange resin(0.5 g.) and scintillation fluid (10 ml. of a 0.5% solution of2,5-diphenyloxazole in a 1:2 mixture of Triton X-100 and toluene) wasadded and the H- adenosine measured by counting the scintillationproduced by the tritium H). The estimation was repeated, using variousconcentrations of the new compounds of formula I, and compared with theresult obtained in the absence of the new compounds.

The new compounds caused 50% inhibition of the hydrolysis caused by thephosphodiesterase at concentrations of, for example, 5 10- to 5 X10"- M.

Preferred compounds of the present invention are those 8-azapurin-6-onederivatives of general formula I wherein R represents a phenyl ornaphthyl group which may optionally carry one, two or three substituentsselected from halogen atoms, and hydroxy, alkyl, phenylalkyl, alkoxy,alkenyloxy, alkoxyalkoxy, phenoxy, phenoxy substituted by an alkoxygroup, aralkoxy, alkylthio, nitro, alkanesulphony], amino,trifluoromethyl, methylenedioxy, and di- 10 alkylamino groups, or Rrepresents a cycloalkyl group containing 3 to 8 carbon atoms, astraightor branchedchain alkyl group containing from 2 to 10 carbonatoms, or a straightor branched-chain alkyl group containing 1 to 10carbon atoms carrying one or two substituents selected from halogenatoms, hydroxy, alkoxy groups containing from 1 to 6 carbon atoms,cycloalkyl groups con taining 3 to 8 carbon atoms and phenyl groups. Ofsuch compounds those of outstading importance are the 8- azapurin-6-onederivatives represented by the general formula:

0 H a \N XXVII wherein R represents a hydroxy group, a straight orbranched-chain alkoxy group containing from 1 to 6 carbon atoms, astraightor branched-chain alkenyloxy group containing from 2 to 6 carbonatoms or an aralkoxy (e.g. phenylalkoxy) group in which the alkoxyportion contains from 1 to 6 carbon atoms and may be straightorbranched-chain, for example a benzyloxy group, R represents a fluorine,chlorine or bromine atom, a trifiuoromethyl group, a hydroxy group, anitro group, a straightor branched-chain alkyl or alkoxy groupcontaining from 1 to 6 carbon atoms, or an aralkoxy (e.g. phenylalkoxy)group in which the alkoxy portion con tains from 1 to 6 carbon atoms andmay be straightor branched-chain, for example a benzyloxy group, and mrepresents 0, 1 or 2, the atoms or groups represented by the symbol Rbeing the same or different when m represents 2, and theirpharmaceutically acceptable salts.

The most important compounds of general formula XXVII are 8-aza-2-(2-hydroxyphenyl) purin-6-one,

8-aza-2- (2-ethoxyphenyl) purin-6-one,

8-aza-2-( 2-isopropoxyphenyl) -purin-6-one,

8-aza-2- (2-n-butoxyphenyl) purin-6-one,

8-aza-2- (Z-sec-bntoxyphenyl) purin-G-one,

8 -aza-2- (2-isobutoxyphenyl) purin--one,

8-aza-2- (2-n-p entyloxyphenyl) purin-6-one,

8-aza-2- (2-isopentyloxypheny1) purin-6-one,

8-aza-2- (5 -rert-butyl-2-methoxyphenyl) purin-6-one,

8-aZa-2- (Z-n-hexyloxyphenyl) purin-6-one,

8-aza-2- (2-benzyloxyphenyl) purin-6-one,

8-aza-2- (5 -hydroxy-2-methoxyphenyl purin-6-one,

8-aza-2- (2,4-dimethoxyphenyl purin-6-one,

8-aza-2- 2,5 -dimethoxyphenyl) purin-6-one,

S-az a-2- 2,5 -dib enzyloxyphenyl) purin-6-one,

8-aza-2- (S-b enzyloxy-Z-methoxyphenyl) purin-6-one,

8-aza- 2- (2,5 -dihydroxyphenyl) purin-6-one,

8-aza-2- (2-methoxy-5-methylphenyl purin-6-one 8-aza-2-(2-methoxy-5-nitrophenyl purin-6-one,

8-aza-2- 2-methoxy-3 ,5 -dinitrophenyl) purin-6-one,

8-aza-2- (2-methoxy-S-trifluoromethylphenyl) purin-6- one,

8 -aza-2- (Z-meth oxy-3 S-dimethylphenyl) purin-G-one,

8-aza-2- (2-allyloxyphenyl) -purin-6-one,

and especially 8-aza-2- (Z-methoxyphenyl purin-6-one and 8-aza-2-(2-prop oxyphenyl) purin-6-one,

and their pharmaceutically acceptable salts.

Other important compounds according to the present invention are 8aza-2-phenylpurin-6-one, 8-aza-2-(3-nhexyloxyphenyl)purin 6 one, 8aza-2-(3-trifluoromethylphenyl)purin 6 one, 8-aza-2-(3-methylphenyl)purin-6-one, and their pharmaceutically acceptable salts.

The following Examples illustrate the preparation of the8-azapurin-6-one derivatives of the present invention.

EXAMPLE 1 A solution of concentrated hydrochloric acid (50 ml.) in water(50 ml.) was stirred and maintained at C. and treated with sodiumnitrite (1.5 g.). The resultant solution was stirred and maintained at 0C. and treated with 4,5-diamino-2-(2 methoxyphenyl) pyrimid-6-one (2.54g.) during 30 minutes, followed by a further quantity of sodium nitrite(1.5 g.). The stirred mixture was then allowed to warm to roomtemperature, when the solid was filtered off, washed with water anddissolved in a dilute aqueous solution of ammonia. The solution wasfiltered and brought to pH 6 by the addition of glacial acetic acid. Theresultant solid was filtered off, washed well with water, sucked dry,and recrystallised from methanol to give 8aza-2-(2-methoxyphenyl)purin-6-one (1.9 g.), m.p. 239 C. (withdecomposition).

Further purification was elfected by recrystallisation of an aliquotfrom pyridine, followed by washing with dilute hydrochloric acid andwith water, to give 8-aza-2- (Z-methoxyphenyl)purin-6-one, m.p. 254-255C. (with decomposition).

By proceeding in a similar manner, but substituting 4,5 -diamino-2-3-methoxyphenyl) pyrimid-6-one,

4,5-diamino-2- (4-methoxyphenyl) pyrimid-G-one,

4,5 -diamino-2-phenylpyrimid-6-one,

4,5 -diamino-2- 2-tolyl) pyrimid-6-one,

4,5-diamino-2- 3-tolyl) pyrimid-6-one,

4,5 -diamino-2- 4-tolyl pyrimid-G-one,

4, 5 -diamino -2- 2-chlorophenyl pyrimid- 6-one,

4,5 -diamino-2- 4-chlorophenyl pyrimid-6-one,

4,5-diamino-2- (2-bromophenyl pyrimid-60ne,

4,5 -diamino-2- 2-fiuoropheny1) pyrimid-6-one,

4, 5 -diamino-2- 4-hydroxyphenyl) pyrimid-fi-one,

crude 4,5-diamino-2-(2-ethoxyphenyl)Py imid-6-one,

crude 4,5 -diamino-2- (2-propoxyphenyl) pyrimid-6-one,

crude 4,5-diamino-2-(2-isopropoxyphenyl)pyrimid-6- one,

crude 4,5-diamino-2- (2-butoxyphenyl) pyrimid-G-one,

4,5 -diamino-2- (2-isobutoxyphenyl) pyrimid-6-one,

crude 4,5 -diamino-2-( Z-sec-butoxyphenyl) pyrimid-6-one,

4,5 -diamino-2- (2-pentyloxyphenyl) pyrimid-6-one,

4,5 -diamino-2- (2-isopentyloxyphenyl pyrimid-6-one,

4,5-diarnino-2-( 2-hexyloxyphenyl) pyrimid-6-one,

4, S-diarnino-Z- 3 -l1exyloxyphenyl pyrimid- 6- one,

4,5-diamino-2- (4-hexyloxyphenyl) pyrimid-G-one,

crude 4,5 diamino -2- [2- (2-ethoxyethoxy phenyl] pyrimid-6-one,

crude 4,5-diamino-2- 2-methylmercaptophenyl) pyrimid- 6-one,

4,5 -diarnino-2- 3-methylmercaptophenyl) pyrimid-6-one,

4,5 -diamino-2- 2-phenoxyphenyl) pyrimid-G-one,

4, 5 -diamino-2- [2- (4-methoxyphenoxy) phenyl] pyrimid- 6-one,

4,5 -diamino-2- 2-benzyloxyphenyl pyrimid-6-one,

4,5 -diamino-2- (Z-methanesulphonylphenyl) pyrimid- 6-one,

4,5-diamino-2- (4-methanesulphonylphenyl) pyrimid-G- one,

4,5-diamino-2-( Z-butanesulphonylphenyl) pyrimid-6- one,

4,5 -diamino-2- 3-trifiuoromethylphenyl pyrimid-6-one,

crude 4,5-diamino-2-(Z-dimethylaminophenyl)pyrimid-G- one,

4,5 -diamino-2- B-dimethylaminophenyl pyrimid-6-one,

4,5-diamino-2- 2,3-dirnethoxyphenyl) pyrimid-6-one,

4,5 -diamino-2- 2,4-dimethoxyphenyl) pyrimid-fi-one,

4,5 -diamino-2- 2,5 -dimethoxyphenyl pyrimid-6-one,

4,5 -diamino-2- 2,6-dimethoxyphenyl) pyrimid-G-one,

4,5-diamino-2- 3,4-dimethoxyphenyl) pyrimid-6-one,

4,5 -diamino-2- 3,5 -dimethoxyphenyl) pyrimid-6-one,

crude 4,5-diamino-2-(4-benzyloxy-Z-methoxyphenyl) pyrimid-6-one,

1 2 4,5 -diamino-2- 5 -b enzyloxy-Z-methoxyphenyl) pyrimid- 6-one,4,5-diamino-2- (2,5 -dibenzyloxyphenyl) pyrimid-G-one, crude4,5-diamino-2- (2-methoxy-5-trifiuoromethylpheny1) pyrimid-G-one, crude4,5 -diamino-2- (2,3-methylenedioxyphenyl) pyrimid-6-one,4,5-diamino-2-(1-naphthy1)pyrimid-6-one and 4,5-diamino-2- (2-naphthylpyrimid-6-one for the 4,5 diamino-2-(2-methoxyphenyl)pyrimid-G-one usedas a starting material in the above preparation, there were prepared8-aza-2-(3-methoxyphenyl)purin-fi-one, m.p. 272273 C.

(with decomposition), 8-aza-2-(4-methoxyphenyl)purin-6-one, m.p. 272 C.

(with decomposition), 8-aza-2-phenylpurin-6-one, m.p. 280 C. (withdecomposition), 8-aza-2-(2-to1y1)purin-6-one, m.p. 263-265 C.,8-aza-2-(3-tolyl)purin-6-one (which contained 0.25 moles of water ofcrystallisation), m.p. 280-281 C., 8-aza-2-(4-tolyl)purin-6-one, m.p.285287 C., 8-aza-2-(2-chlorophenyl)purin-6-one, m.p. 268270 C.,8-aza-2-(4-chlorophenyl)purin-6-one, m.p. 294 C.

(with decomposition), 8-aza-2-(2-bromophenyl)purin-6-one, m.p. 247250C., 8-aza-2-(2-fluorophenyl)purin-fi-one, m.p. 251.5-

252.5 C., 8-aza-2-(4-hydroxyphenyl)purin-6-one (which contained 0.2 moleof acetic acid of crystallisation), m.p. 330

C. (with decomposition), 8-aZa-2-(2-ethoxyphenyl)purin-6-one, m.p.2l6218 C.

(with decomposition), 8-aza-2- 2-propoxyphenyl) purin-fi-one, m.p. 238-240 C., 8-aza-2-(2-isopropoxyphenyl)purin-6-one, m.p. 218- 219 C.(with decomposition), 8-aza-2-(2-butoxyphenyl)purin-6-one, m.p. 188-190C., 8-aza-2-(Z-iso-butoxyphenyl)purin-6-one, m.p. 226-227 C. (withdecomposition), 8-aza-2-(Z-sec-butoxyphenyl)purin-6-one, m.p. 205-208 C.(with decomposition), 8-aza-2-(Z-pentyloxyphenyl)purin-6-one, m.p.175176 8-aza-2-(Z-isopentyloxyphenyl)purin-6-one, m.p. 186- 188 C. (withdecomposition), 8-aza-2-(2-hexyloxyphenyl)purin-6-one, m.p. -132 C.,8-aza-2-(3-hexyloxyphenyl)purin-6-one, m.p. 220- 221 C.,8-aza-2-(4-hexyloxyphenyl)purin-6-one, m.p. 225 C.

(with decomposition), 8-aza-2-[2-(2-ethoxyethoxy)pl1enyl]purin-6-one,m.p.

162-164 C., 8-aza-2-(Z-methoxymercaptophenyl)purin-6-one monohydrate,m.p. 223226 C., 8-aza-2-(3-methylmercaptophenyl)purin-6-one (whichcontained 0.75 mole of water of crystallisation), m.p. 278.5280 C., 8-aza-2-(Z-phenoxyphenyl)purin-6-one, m.p. 224- 227 C., 8-aza-2-[2-(4-methoxyphenoxy)phenylJpurin-G-one monohydrate, m.p. 249-250 C.,8-aza-2-(2-benzyloxyphenyl)purin-6-one, m.p. 240- 242 C. (withdecomposition), 8-aza-2-(Z-methanesulphonylphenyl)purin-6-0ne, m.p.

274275 C. (with decomposition),8-aza-2-(4-methanesulphonylphenyl)purin-6-one, m.p.

310315 C. (with decomposition), 8-aza-2-(2-butanesulphonylphenyl)purin-6-one, m.p.

282 C. (with decomposition), 8-aza-2-(3-trifluoromethylphenyl)purin-6-one, m.p. 268

C. (with decomposition),

crude 4,5-diamino-2-(2-propoxyphenyl)pyrimid-6-one,

crude 4,5 -diamino-2- 2-isopropoxyphenyl pyrimid-G-one [characterised asthe picrate containing 0.5 moles of acetic acid of crystallisation, m.p.192l93 C. (with decomposition) crude 4,5-diamino-2-(2butoxyphenyl)pyrimid-6-one,

4,5-diamino-2-(2-isobutoxyphenyl)pyrimid-6-one, m.p.

164-166 C. (with decomposition),

crude 4,5-diamino-2-(2-sec-butoxyphenyl)pyrimid-6-one,

4,5 -diamino-2-(2-pentyloxyphenyl)pyrimid-6-one, m.p.

4,5-diamino-2-(2-isopentyloxyphenyl) pyrimid-6-one, m.p.

4,5-diamino-2-(2-hexyloxyphenyl)pyrimid-6-one, m.p.

ISO-152 C. (with decomposition),

4,5diamino-2-(3-hexyloxyphenyl)pyrimid-6-one, m.p.

4,5-diamino-2- (4-hexyloxyphenyl) pyrimid--one, m.p.

l75l76 C.,

crude, 4,5-diamino-2- [2- 2-ethoxyethoxy phenyl] pyrimid-6-one,

4,5-diamino-2-(2-methylmercaptophenyl)pyrimid-6-one,

m.p. 227-229 C.,

4,5-diamino-2-(3-methylmercaptophenyl)pyrimid-6-one,

m.p. 246-250 C. (with decomposition),

4,5-diamino-2-(2-phenoxyphenyl) pyrimid-6-one, m.p.

4,5 -diamino-2 [2- 4-methoxyphenoxy) phenyl] pyrimid- 6-one, m.p.195-200 C.,

4,5-diamino-2-(Z-benzyloxyphenyl)pyrimid-6-one, m.p.

165-167 C. (with decomposition),

4,5-diamino-2-(2-methanesulphonylphenyl)pyrimid-6- one, m.p. 262-265 C.,

4,5-dia'mino-2-(4-methanesulphonylphenyl)pyrimid-6- one, m.p. 282-285 C.(with decomposition),

4,5-diamino-2-(Z-butanesulphonylphenyl)pyrimid-6-one,

m.p. 236-237 C.,

4,5-diamino-2-(3-trifiuoromethylphenyl)pyrimid-6-one,

m.p. 235238 C.,

crude 4,5-diamino-2-(Z-dimethylaminophenyl)pyrimid- 6-one,

4,5-diamino-2-(3-dimethylaminophenyl)pyrimid-6-one hemihydrate, m.p.127130 C.,

4,5-diamino-2-(2,3-dimethoxyphenyl)pyrimid-6-one,

m.p. 74-76 C.,

4,5-diamino-2-(2,4-dimethoxyphenyl) pyrimid-G-one, m.p.

193 C. (with decomposition),

4,5-diamino-2-(2,5-dimethoxyphcnyl) pyrimid-6-one, m.p.

4,5 -diamino-2- (2,6-dimethoxyphenyl) pyrimid-6-one, m.p.

4,5-diamino-2-(3,4-dimethoxyphenyl)pyrimid-6-one, m.p.

245249 C. (with decomposition),

4,5-diamino-2-(3,5-dimethoxyphenyl)pyrimid-6-one, m.p.

235-240 C. (with decomposition),

crude 4,5-diamino-2-(4-benzyloxy-Z-methoxyphenyl) pyrimid-6-one,

4,5-diamino-2-(5-benzyloxy-Z-methoxyphenyl)pyrimid-6- one m.p. 204-208"C.,

4,5 -diamino-2- 2,5 -dibenzyloxyphenyl) pyrimid-6-one,

m.p. 128132 C.,

crude 4,5-diamino-2-(2-methoxy-S-trifluoromethylphenyl)pyrimid-6-one,

crude 4,5-diamino-2- (2,3 methylenedioxyphenyl) pyrimid- 6-one,

4,5-diamino-2-(1-naphthyl)pyrimid-6-one, m.p. 246- 248 C., and

4,5-diamino-2-(Z-naphthyl)pyrimid-6-one, m.p. 257- respectively.

The 4,5 diamino-2-(2emethoxyphenyl)pyrimid-6-one, used as a startingmaterial in the above preparation, was alternatively prepared asfollows:

4 Amino 2 (Z-methoxyphenyl)-5-nitrosopyrimid-6- one (56 g.) wassuspended in water (2000 ml.). Triethylamine (50 ml.) was added, and themixture was stirred at room temperature for 30 minutes. Undissolvedstarting material (4 g.) was removed by filtration, the filtrate wascooled in ice-water and sodium dithionite (75 g.) was added in portionsduring 20 minutes with stirring, keeping the temperature of the mixturebelow 10 C. After stirring for a further minutes at 0-10" C., the4,5-diamino-2-(Z-methoxyphenyl)pyrimid 6-one (47 g.'), m.p. 208-210 C.(with decomposition), was filtered off, washed with water, and dried invacuo. This material was pure enough for use as a starting material inthe next stage of the synthesis. 1

The 4-amino-2-(Z-methoxyphenyl)-5-nitrosopyrimid-6- one, used as astarting material in the above preparations was prepared as follows:

A stirred solution of sodium methoxide in dry methanol [prepared fromsodium (10.7 g.) and dry methanol ml.)] maintained at 0 C. was treatedwith 2- methoxybenzamidine hydrochloride (21.6 g.) followed by ethylot-oximinocyanoacetate (16.5 g.). The mixture was then heated to refluxwith stirring for 4.5 hours, and then poured into water (1000 ml.) andbrought to pH 6 by by the addition of glacial acetic acid. The resultantgreen solid was filtered oil and recrystallised from aqueous acetic acidto give 4-amino-2-(Z-methoxyphenyl)-5- nitrosopyrimid-6-one (19.2 g.),m.p. 210-211 C. (with decomposition). A further quantity of less pure4-amin0- 2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (2.9 g.) wasobtained by concentration of the mother liquors of therecrystallisation.

By proceeding in a similar manner, but substituting 3-methoxybenzamidine, 4-methoxybenzamidine hydrochloride, benzamidinehydrochloride (prepared as described by P. E. Fanta & E. A. Tedman, J.Amer. Chem. Soc., 1956, 78, 1434), 2-toluamidine (prepared as describedby J. Weinstock, R. Y. Dunotf & J. G. Williams, J. Medicin. Chem., 1968,11, 542), 3-to1uamidine hydrochloride (prepared as described by J. B.Ekeley, D. V. Tieszen & A. Ronzio, J. Amer. Chem. Soc., 1935, 57, '381),4-toluamidine hydrochloride (prepared as described by A. V. Kirsanov &T. M. Polyakova, Bull. Soc. Chim. France, 1936 (5) 3, 1600),2-chlorobenzamidine hydrochloride (prepared as described by L.Weintraub, S. -R. Oles and N. Kalish, J. Org. Chem., 1968, 33, (1679),4-chlorobenzamidine hydrochloride (prepared as described by P. E- Fanta& E. A. Hedman, J. Amer. Chem. Soc., 1956, 78, 1434), 2-bromobenzamidinehydrochloride, Z-fluorobenzamidine hydrochloride, 4-hydroxybenzamidinehydrochloride (prepared as described by M. W. Partridge & W. F. Short,J. Chem. Soc., 1947, 390), 2-ethoxybenzamidine (prepared as described byL. Weintraub, S. R. Oles & N. Kalish, J. Org. Chem., 1968, 33, 1679),2-propoxybenzamidine hydrochloride, crude 2-isopropoxybenzamidine, crude2-butoxybenzamidine fluorosulphonate, crude 2-isobutoxybenzamidine,crude 2 sec butoxybenzamidine, crude 2 pentyloxybenzamidine, 2isopentyloxybenzamidine hydrochloride, 2-hexyloxybenzamidine'hydrochloride, crude 3-hexyloxy-benzamidine, 4-hexyloxybenzamidinehydrochloride (which contained 0.25 moles of water of crystallisation),2-(2-ethoxyethoxy)benzamidine hydrichloride, 2-methylmercaptobenzamidinehydrochloride, 3-methylmercaptobenzamidine hydrochloride, crude2-phenoxybenzamidine, crude 2 (4 methoxyphenoxy) benzamidine, crude2-benzyloxybenzamidine, Z-methan'esulphonylbenzamidine, 4methanesulphonylbenzamidine hydrochloride (prepared as described by P.Oxley, M. W. Partridge, T. D. Robson & W. F. Short, J. Chem.,Soc., 1946,763), 2-butanesulphonylbenzamidine hydrochloride, crude3-trifiuoromethylbenzamidine, crude Z-dimethylaminobenzamidine, 3dimethylaminobenzamidene. hydrochloride, 2,3-dirnethoxybenzamidinefiuorosulphonate, 2,4 dimethoxybenzamidine fluorosulphonate, 2,5dimethoxybenzamidine, 2,6-dimethoxybenzamidine, 3,4-dimethoxybenzamidinehydrochloride (prepared as described by A. P. T. Easson & F. L. Pyman,J. Chem. Soc.,

1931, 2991), 3,5-dimethoxybenzamidine fluorosulphonate, crude 4benzyloxy 2 methoxybenzamidine, crude 5- benzyloxy-Z-methoxybenzamidine,2,5 dibenzyloxybenzamidine, crude2-methoxy-5-trifluoromethylbenzamidine, crude 2,3rnethylenedioxybenzamidine, l-naphthamidine hydrochloride (prepared asdescribed by P. Oxley & W. -F. Short, J. Chem. Soc., 1946, 147) and2-naphthamidine hydrochloride (prepared as described by A. Pinner, F.Klein & P. Lohmann, Ber. 1878, 11, 1475).

For the 2-methoxybenzamidine hydrochloride used as a starting materialin the above preparation, there were prepared:

4-amino-2-(3-methoxyphenyl)-5-nitrosopyrimid- 6-one, m.p. 259 C. (withdecomposition),

4-amino-2- 4-methoxyphenyl -5-nitrosopyrimid- 6-one, m.p. 275-278 C.(with decomposition),

4amino-5-nitroso-2-phenylpyrimid-6-one, m.p.

261-262 C. (with decomposition),

4-amino-5-nitroso-2-(2-tolyl)pyrimid-6-one, m.p.

4-amino-5-nitr0so-2-(3-tolyl)pyrimid-6-one, m.p.

crude 4-amino-5-nitroso-2-(4-toly1)pyrimid-6-one,

crude 4-amino-2-(2-chlorophenyl) -5-nitrosopyrimid- 6-one,

4-amino-2-(4-chlorophenyl)-5-nitrosopyrimid- 6-one, m.p. 269-270 C.(with decomposition),

4-amino-2-(2-bromophenyl)-5-nitroso-pyrimid- '6-one, m.p. 165-170 C.,

4-amino-2- (2-fluoropheny1)-5-nitrosopyrimid-6-one,

m.p. 257.5-258.5 C.,

4-amino-2- (4-hydroxypheny1 -5-nitrosopyrimid- 6-one, m.p. above 300 C.,

4-arnino-2- (2-ethoxypheny1) -5-nitrosopyrimid-6-o ne,

m.p. 22l-222 C.,

4-amino-5-nitroso-2-(2-propoxyphenyl)pyrimid-6-one,

m.p. 206-207 C.,

4-amino-2-(2-isopropoxyphenyl)-5-nitrosopyrimid- 6-one, m.p. 208-209 C.(with decomposition),

crude 4-amino-2-(2-butoxyphenyl)-5-nitrosopyrimid- 6-one,

4-amino-2- 2-isobutoxyphenyl) -5-nitrosopyrimid- 6-one,m.p. 233-235 C.(with decomposition),

4-amino-2- (Z-sec-butoxyphenyl) -5-nitrosopyrimid- 6-one, m.p. 186-187"C.,

4-amino-5-nitroso-2-(Z-pentyloxyphenyl)pyrimid- 6-one, m.p. 223-224 C.,

4-amino-2- (Z-isopentyloxyphenyl) -5-nitros opyrimid- 6-one, m.p.212-214 C. (with decomposition),

4-amino-2-(2-hexyloxyphenyl)-5-nitrosopyrimid-6-0ne,

m.p. 184-185 C.,

4-amino-2- 3 -hexy1oxypheny1) --nitrosopyrimid-6- one, m.p. 225 C. (withdecomposition),

4-amino-2-(4-hexyloxyphenyl)-5-nitrosopyrimid-6-one,

m.p. 249-250 C. (with decomposition),

4-amin0-2- [2- (2-ethoxyethoxy)pheny1] -5-nitrosopyrimid- 6-one, m.p.194-195 C.,

4-amino-2- Z-methylmercaptophenyl -5-nitrosopyrimid-6-one, m.p.232.5-233.5 C.,

4-amino-2-(3-methylmercaptophenyl)-5-nitrosopyrimid- 6-one, m.p. 238 C.,(with decomposition),

4-amino-5-nitroso-2-(2-phenoxyphenyl)-pyrimid-6- one, m.p. 230 C. (withdecomposition),

crude 4-amino-2-[2-(4-methoxyphenoxyphenyl] -5- nitrosopyrimid-6-one,

4-amino-2-(2-benzyloxyphenyl)-5-nitrosopyrimid-6-one,

225-226 C. (with decomposition),

4-amino-2-(2-methanesulphonylphenyl)-5-nitrosopyrimid-6-one, m.p.264-265 C. (with decomposition),

4-amino-2- (4-methanesulphonylphenyl)-5-nitrosopyrimid-6-one, m.p.295-296.5 C. (with decomposition),

4-amin0-2- (Z-butanesulphonyl) -5-nitrosopyrimid- 6- one, m.p. 254 C.(with decomposition),

4-amino-5-nitroso-2-(3-trifluoromethylphenyl)pyrimid- 6-one, m.p. 263 C.(with decomposition),

4-amino-2- (Z-dimethylaminophenyl) -5-nitro sopyrimid- 6-one, m.p.2l2-213 C. (with decomposition),

4-amin0-2- 3-dimethylaminophenyl) -5-nitrosopyrimid- 6-0ne, m.p. 215-219C.,

crude 4-amino-2-(2,3-dimethoxyphenyl)-5-nitrosopyrimid-6-one,

4-amino-2-(2,4-dimethoxyphenyl)-5-nitrosopyrimid- 6-one, m.p. 225 C.,

4-amino-2- (2,5-dimethoxyphenyl) -5-nitrosopyrimid-6- one, m.p. 250 C.(with decomposition),

4-amino-2-(2,6-dimethoxyphenyl)-5-nitrosopyrimid- 6-one, m.p. 260 C.(with decomposition),

4-amino-2-(3,4-dimethoxyphenyl)-5-nitrosopyrimid- 6-one, m.p. 27'8-280C. (with decomposition),

crude 4-amino-2-(3,5-dimethoxyphenyl) -5-nitrosopyrimid-6-one,

crude 4-amino-2-(4-benzyloxy-Z-methoxyphenyl) -5- nitrosopyrimid-6-one,

4-amino-2- (S-benzyloxy-2-methoxyphenyl) -5-nitroso pyrimid-6-one, m.p.228.5 C. (with decomposition),

4-amino-2- (2,5 -dibenzy1oxyphenyl) -5-nitrosopyrimid 6-one, m.p.169-170 C.,

crude 4-amino-2-(2-methoxy-S-trifiuoromethylphenyl)-5-nitrosopyrimid-6-one,

4-amino-2- 2,3-methylenedioxyphenyl) -5-nitrosopyrimid-6-one, m.p. 210C. (with decomposition),

4-amino-2-( l-naphthyl) -5-nitrosopyrimid.-6-one,

m.p. 256-257 C., and

4-amino-2-(2-naphthyl)-5-nitrosopyrimid-6-one, m.p.

282 C. (with decomposition),

respectively.

The Z-methoxybenzamidine hydrochloride used as starting material in theabove preparation was prepared as follows:

To a solution of hydroxylarnine hydrochloride (245 g.) and sodiumcarbonate (170 g.) in water (2.6 l.) was added a solution of2-methoxybenzonitrile (127.5 g.) in ethanol (1.25 1.), and the mixturerefluxed with stirring for 1.5 hours. The solution was concentrated invacuo to low bulk and the resultant oil crystallised on standing. Thesolid was filtered off, Washed with water to remove inorganic salts,dried at 60 C., and recrystallised from benzene to give2-methoxybenzamidoxime (49.2 g.), m.p. 117-119 C. Further material (21.2g., m.p. 119-120" C.) was obtained by concentration of therecrystallisation mother liquor.

A solution of 2-methoxybenzamidoxime (70.4 g.) in ethanol (500 ml.) wascatalytically reduced at 70 p.s.i. pressure using Raney nickel catalyst"(14 g.). The solution was concentrated in vacuo to approximately m1.,diluted with dry diethyl ether (300 ml.), and a saturated solution ofhydrogen chloride in diethyl ether (300 m1.) added with ice-cooling. Theresultant precipitate was filtered ofi, washed well with dry diethylether, and dried in vacuo over silica gel to give 2-methoxybenzamidinehydrochloride (64.5 g.), m.p. 156-159 C.

The Z-methoxybenzonitrile may be prepared as described by F. Ahrens,Ben, 1887, 20, 2955.

By proceeding in a similar manner, but substituting2-propoxybenzamidoxime (prepared as described by A. A. Aroyan and S. P.Kocharyan, Izv. Akad. Nauk. Arm. S.S.R., Khim. Nauki, 1964, 17, 543),for the 2-methoxybenzamidoxime used as an intermediate in the abovereaction, there was prepared 2-propoxybenzamidine hydrochloride, m.p.169-171 C.

By again proceeding in a similar manner, but substituting3-methoxybenzonitri1e (prepared as described by O. L. Mndzhoyan and G.M. Pogosyan, Izv. Akad. Nauk. Arm. S.S.R., Khim. Nauki, 1963, 16, 263),4-hexyloxybenzonitrile (prepared as described by M. W. Partridge,

J. Chem. Soc., 1949, 3043), 2-(2-ethoxyethoxy)benzonitrile [prepared asdescribed by Karl Thomae G.m.b.H. Chimisch Pharmazeutische Fabrik, B.P.774,635 (1957)], 2-methylmercaptobenzonitrile (prepared as described byT. Zincke & G. Siebert, Ber., 1915, 48, 1242),Z-methanesulphonylbenzonitrile, 2-butanesulphonylbenzonitrile, 2-dimethylaminobenzonitrile (prepared as described by P. Grammaticakis,Bull. Soc. Chim. France, 1953, 207), 2,S-dimethoxybenzonitrile (preparedas described by H. Kauffmann & A. Grombach, Liebigs Annalen der Chemie,1906, 344, 71) and 2-methoxy-5-trifiuoromethylbenzonitrile.

For the Z-methoxybenzonitrile used as a starting material in the abovepreparation, there were prepared respectively:

3-methoxybenzamidoxime, m.p. 101-103 C.,

3-methoxybenzamidine, m.p. 161-l63 C.,

4-hexyloxybenzamidoxime, m.p. 88-90 C.,

4-hexyloxybenzamidine hydrochloride (which contained 0.25 moles of waterof crystallisation), m.p. l03 104 C.,

crude 2-(2-ethoxyethoxy)benzamidoxime, 2-(2-ethoxyethoxy)benzamidinehydrochloride, m.p. 124-125 C.,

2-methylmercaptobenzamidoxime, m.p. 170-172 C.,

2-methylmercaptobenzamidine hydrochloride, m.p. 157-Z-methanesulphonylbenzamidoxime, m.p. 225-226 C.,

2-methanesulphonylbenzamide, m.p. 173 C. (with decomposition),

2-butanesulphonylbenzamidoxime, m.p. 134l36 C.,

Z-butanesulphonylbenzamidine hydrochloride, m.p.

2-dimethylaminobenzamidoxime, m.p. 134-136 C.,

crude Z-dimethylaminobenzamidine, 2,5-dimethoxybenzamidoxime, m.p. 173C.,

2,5-dimethoxybenzamidine, m.p. 105 C.,

2-methoxy-5-trifluoromethylbenzamidoxime, m.p. 119- 120 C. and

crude 2-methoxy-5-trifluoromethylbenzamidine.

The 2-hexyloxybenzamidine hydrochloride used as a starting material inthe above preparation was prepared as follows:

To a solution of 2-hexyloxybenzamide (64 g.; prepared as described by E.M. Bavin, F. J. Macrae, D. E. Se'ymour and P. D. Waterhouse, J. Pharm.Pharmacol, 1952, 4, 872) in anhydrous methylene chloride (830 ml.) wasadded, dropwise during 10 minutes with stirring, a solution oftriethylogzonium borofluoride (55.2 g.) in anhydrous methylene chloride(170 ml.). The solution was stirred for a further 105 minutes, andallowed to stand at room temperature for 2 days. The solution wasconcentrated to 350 ml., and anhydrous diethyl ether (1750 ml.) wasadded. The precipitated solid was filtered off and washed with anhydrousdiethyl ether to give ethyl 2-hexy1oxybenzimidate borofiuoride (62 g.),m.p. 68-70 C., which was pure enough to use for the next stage of thesynthesis. A pure sample, m.p. 73-74 C., was obtained byrecrystallisation of an aliquot from a mixture of anhydrous methylenechloride and anhydrous diethyl ether.

A mixture of ethyl 2-hexyloxybenzimidate borofluoride (61 g.) andanhydrous ethanolic ammonia (90 ml.; prepared by saturation of anhydrousethanol with anhydrous ammonia at C.) was left to stand for 4 days. Thesolid which separated was filtered off and washed with anhydrousethanol. The combined filtrate and washings were evaporated to drynessand the solid residue was treated with water (60 ml.) and SN sodiumhydroxide solution (120 ml.). The oil which separated was extracted withdiethyl ether, the extract dried over anhydrous potassium carbonate, andevaporated. The oily residue was dissolved in anhydrous diethyl ether(250 ml.) and an anhydrous ethanolic solution of hydrogen chloride ml.;prepared by saturation at 0 C.) was added. The precipitated solid wasfiltered off, washed with anhydrous diethyl ether, and dried at 60 C. togive 2-hexyloxybenzamidine hydrochloride (44 g.), m.p. 155-158 C. Thiscompound may be further purified by recrystallisation from 2Nhydrochloric acid.

By proceeding in a similar manner, but substituting2-isopropoxybenzamide (prepared as described by E. M. Bavin, F. J.Macrae, D. E. Seymour and P. D. Waterhouse, J. Pharm. Pharmacol, 1952,4, 872), 2-isobutoxybenzamide, Z-sec-butoxybenzamide (prepared asdescribed by L. V. Coates, D. J. Drain, J. A. Kerridge, F. J. Macrae andK. Tattersall, J. Pharm. Pharmacol, 1957, 9, 855),2-isopentyloxybenzamide (prepared as described by J. A. Faust, L. H.Jules and M. Sahyun, J. Amer. Pharm. Assoc., 1956, 45, 514),3-hexyloxybenzamide (prepared as described by L. V. Coates, D. J. Drain,F. J. Macrae and K. Tattersall, J. Pharm Pharmacol, 1959, 11, Suppl.240T), 2-bromobenzamide (prepared as described by C. Schotten, Ber.,1888, 21 2235), 2-fluoroben2amide (prepared as described by H. Meyer &A. Hub, Monatsh., 1910, 31, 936), 2-benzyloxybenzamide (prepared asdescribed by J. A. Faust, L. H. Jules and M. Sahyun, J. Amer. Pharm.Assoc., 1956, 45, 514) and 2,5-dibenzyloxybenzamide.

For the Z-hexyloxybenzamide used as a starting material in the abovepreparation, there were prepared respectively:

ethyl 2-isopropoxybenzimidate borofluoride, m.p. 130- crude2-isopropoxybenzamide (characterised as its picrate,

mp. 188-189 C.),

ethyl 2-isobutoxybenzimidate borofluoride, m.p. 108- crude2-isobutoxybenzamidine (characterised as its pic rate, m.p. 187188 C.),

ethyl Z-sec-butoxybenzimidate borofluoride, m.p. 73-

crude Z-sec-butoxybenzamidine (characterised as its picrate, m.p.159-16l C.),

ethyl Z-isopentyloxybenzimidate borofluoride, m.p. 120.5-

2-isopentyloxybenzamidine hydrochloride, m.p. 156- crude ethyl3-hexyloxybenzimidate borofluoride,

crude 3-hexyloxybenzamidine,

crude ethyl 2-bromobenzimidate borofluoride,

2-bromobenzamidine hydrochloride, m.p. 303305 C crude ethyl2-fiuorobenzimidate borofluoride,

Z-fluorobenzamidine hydrochloride, m.p. 168171 Cethlylls2-benzyloxybenzimidate borofluoride, m.p. 117- crude2-benzylox'ybenzamidine (characterised in the form of the picrate, m.p.184-185 C.),

crude ethyl 2,5-dibenzyloxybenzimidate borofluoride and2,5-d1benzyloxybenzamidine, m.p. 102-108 C The 2-isobutoxybenzamide usedas a starting material the above preparation was prepared as follows:

Salicylamide (68.5 g.; prepared as described by R. Bogoczek, Farm.Polska, 1960, 16, 26) was added to a solution of sodium (11.5 g.) inanhydrous ethanol (400 ml.). Isobutyl bromide (60 ml.) was then added,and the mixture was stirred and heated to reflux overnight. The ethanolwas evaporated, and sufiicient water was added to the residue todissolve the sodium bromide. The oil which did not dissolve wasextracted with chloroform, the extract was washed twice with 2N sodiumhydroxide solution and once with water, dried over magnesium sulphate,filtered and evaporated. The residue was triturated with light petroleum(b.p. 40-60 C.) to give 2-isobutoxybenzamide, which was pure enough foruse in the next stage of the synthesis. A pure sample, m.p. -128 21 C.,was obtained by recrystallisation of an aliquot from cyclohexane.

The 2,6-dimethoxybenzamidine used as a starting material in the abovepreparation was prepared as follows:

A mixture of 2,6-dimethoxybenzamide (68 g.; prepared as described by P.Grammaticakis, Compt. rend, 1968, 267C, 152) methyl fluorosulphonate (45g.) and anhydrous methylene dichloride (1 l.) was stirred at roomtemperature for 3 hours. The solution was evaporated in vacuo, and theresidue treated with anhydrous diethyl ether to give crude methyl2,6-dimethoxybenzimidate fluorosulphonate as a white solid, M.P. 115137C. ThlS was dissolved in anhydrous ethanol ('1 l.) and the solution wascooled to C. Anhydrous ethanolic ammonia (350 ml.; prepared bysaturation of anhydrous ethanol with anhydrous ammonia at 0 C.) wasadded, and the mixture kept at room temperature for 4 days. The solutionwas filtered, the filtrate was evaporated in vacuo, the residue wastreated with an excess of 2N sodium hydroxide solution, and theprecipitated solid was filtered off, washed with water andrecrystallised from isopropanol to give 2,6-dimethoxybenzamidine (15g.), M.P. 170174 C.

By proceeding in a similar manner but substituting:

2-butoxybenzamide (prepared as described by E. M.

Bavin, F. J. Macrae, D. E. Seymour and P. D. Waterhouse, J. Pharm.Pharmacol, 1952, 4, 872),

2-pentyloxybenzamide (prepared as described by E. M.

Bavin, F. I. Macrae, D. E. Seymour and P. D. Waterhouse, J. Pharm.Pharmacol, 1952, 4, 872),

2-phenoxybenzamide (prepared as described by G. Lock and F. H. Kempter,Monatsh, 1935, 67, 24),

2- (4-methoxyphenoxy) benzamide,

2,3-dimethoxybenzamide (prepared as described by F.

Mauthner, I. Prakt. Chem., 1926, [2], 112, 64),

2,4-dimethoxybenzamide (prepared as described by P.

Grammaticakis, Bull. Soc. Chim. France, 1965, 848),

3,5-dimethoxybenzamide (prepared as described by F.

Mauthner, J. Prakt. Chem., 1913, [2], 87, 405),

4-benzyloxy-2-methoxybenzamide,

5 benzyloxy-2-methoxybenzarnide and 2,3-methylenedioxybenzamide For the2,6-dimethoxybenzamide used as a starting material in the abovepreparation, there were prepared:

crude 2-butoxybenzamidine fluorosulphonate,

crude 2-penty1oxybenzamidine,

crude 2-phenoxybenzamidine,

crude 2-(4-methoxyphenoxy)benzamidine,

2,3-dimethoxybenzamidine fiuorosulphonate, M.P. 75-

2,4-dimethoxybenzamidine fluorosulphonate, M.P. 193

3,5-dimethoxybenzamidine fluorosulphonate, M.P. 115- crude4-behzyloxy-2-methoxybenzamidine,

crude 5-benzyloxy-Z-methoxybenzamidine and crude 2,3-

methylenedioxybenzamidine respectively.

The 3-methylmercaptobenzamidine hydrochloride used as a startingmaterial in the above preparation was prepared as follows:

A solution of 3-methylmercaptobenzonitrile (26.2 g.; prepared asdescribed by T. Zincke and I. Miiller, Ber., 1913, 46, 775) andanhydrous ethanol (28.4 ml.) in anhydrous chloroform (47.3 ml.) wascooled to 0 C., saturated with anhydrous hydrogen chloride, and themixture kept at 0 C. for 5 days. The solution was evaporated in vacuo,the residue mixed with anhydrous ethanolicv ammonia (200 ml.) and keptat 37 C. for 5 days. The solid was filtered 01f, combined with thatobtained by evaporation of the filtrate and suspended in water (300ml.), brought to pH 11 with concentrated sodium hydroxide solution, andextracted with chloroform. The chloroform extract was washed with water,dried over sodium sulphate, and evaporated. The residue Was dissolved inanhydrous ethanol and saturated ethanolic hydrogen chloride was added,followed by an excess of anhydrous diethyl ether. The solid whichseparated was filtered off. This 3-methylmercaptobenzamidinehydrochloride (23 g.) was pure enough to use in the next stage of thesynthesis. An aliquot was purified by dissolving in anhydrous ethanol,boiling with charcoal, filtering and precipitating with ether, to givepure 3-methylmercaptobenzamidine hydrochloride, M.P. 157-161" C.

By proceeding in a similar manner but substituting 3-dimethylaminobenzonitrile (prepared as described by P. Grammaticakis,Bull. Soc. Chim. France, 1953, 207), and 3-trifluoromethylbenzonitrile(prepared as described by F. Swarts, Chem. Zent., 1898, II, 26) for the3-methylmercaptobenzonitrile used as a starting material in the abovepreparation, there were prepared 3-dimethylaminobenzamidinehydrochloride, M.P. 195198 C. and crude 3-trifluoromethylbenzamidine,respectively.

The 2-methanesulphonylbenzonitrile used as a starting material in theabove preparation was prepared as follows:

2-Methanesulphonylbenzarnide (34 g.) was added to phosphorus oxychlorideml.) and the mixture was refluxed for 90 minutes. The excesss ofphosphorus oxychloride was evaporated in vacuo, and the oily residue wastreated with water (200 ml.), with ice cooling. The solid whichseparated was filtered off, washed with water and rescrystallised fromethanol togive Z-methanesulphonylbenzonitrile (27 g.), M.P. IDS-106 C.

2-Butanesulphonylbenzonitrile, B.P. 225-227 C./ 10 mm. Hg, was preparedsimilarly, from Z-butanesulphonylbenzamide.

The Z-methanesulphonylbenzamide, used as a starting material in theabove preparation, was prepared as follows:

2-Methanesulphonylbenzoic acid (64 g.); prepared as described by P.Oxley, M. W. Partridge, T. D. Robson and W. F. Short, J. Chem. Soc.,1946, 763) and thionyl chloride (200 ml.) were refluxed together for 3hours. The excess of thionyl chloride was evaporated in vacuo, and theresidue was added slowly, in portions, to concentrated aqueous ammoniasolution (400 ml.) with shaking and cooling. After standing at 0 C., thesolid was filtered off and recrystallised from ethanol to giveZ-methanesulphonylbenzamide (36 g.), M.P. 149 C.

Prepared by proceeding in a similar manner were2-butanesulphonylbenzamide, M.P. 102l03 C.,4-benzyloxy-Z-methoxybenzamide, M.P. -122 C.,S-benzyloxy-Z-methoxybenzamide, M.P. 144-146 C.,2,S-dibenzyloxybenzamide, M.P. l53l55 C., 2-(4-methoxyphenoxy)benzamide,M.P. 154155 C., and 2,3-methylenedioxybenzamide, M.P. 174-176 C.,

from Z-butanesulphonylbenzoic acid, 4-benzyloxy-2-methoxybenzoic acid(prepared as described by K. G. Dave, S. A. Telang and K. Vonkataraman,J. Sci. Ind. Res. ('India), 1960, 19B, 470),

5-benzyloxy-2-methoxybenzoic acid,

2,5-dibenzyloxybenzoyl chloride (prepared as described by A. Zane and S.H. Wender, J. Org. Chem., 1964, 29, 2078),

2-(4-methoxyphenoxy)benzoic acid (prepared as described by F. Ullmannand M. Zlokasoif, Ber., 1905, 38, 2117) and 2,3-methylenedioxybenzoicacid (prepared as described by W. H. Perkin and V. M. Trikojus, J. Chem.Soc., 1926, 2925),

respectively.

The Z-butanesulphonylbenzoic acid, used as a starting material in theabove preparation, was prepared as follows:

A solution of Z-butylmercaptobenzoic acid (10.5 g.;

prepared as described by S. E. Livingstone, J. Chem. Soc., 1956, 437) inglacial acetic acid (100 ml.) was heated at 100 C. for 1 hour withhydrogen peroxide (100 vols.; 50 ml.). The solution was evaporated invacuo almost to dryness, and water was added to the residue. The mixturewas extracted with dichloromethane, the extract was dried over anhydroussodium sulphate and filtered, and the filtrate was evaporated. Theresidue was treated with light petroleum (b.p. 4060 C.) and cooled toabout -70 C. The solid was filtered OH and recrystallised from toluene,cooling to about 70 C. and filtering cold, to giveZ-butanesulphonylbenzoic acid (11.0 g.), m.p. 72.5- 73.5 C.

The -benzyloxy-2-methoxybenzoic acid, used as a starting material in theabove preparation, was prepared as follows:

Anhydrous potassium carbonate (60 g.) was added slowly with stirring toa refluxing mixture of S-benzyloxysalicyclic acid (13 g.; prepared asdescribed by H. Bogeny and R. Krattner, Arch. Pharm; 1960, 293, 393) andanhydrous ethanol (250 ml.). Dimethyl sulphate (36 ml.) was then added,and the mixture stirred under reflux for 24 hours. The solid wasfiltered off, and the filtrate evaporated in vacuo to give more solid.The combined solids were suspended in water (250 ml.), and sodiumhydroxide g.) was added. The mixture was stirred under reflux for 2hours, and then concentrated hydrochloric acid was added through thecondenser, at such a rate that the contents of the flask continued toreflux gently, until pH 1 was attained. After being cooled, the solidwhich separated was filtered off, and recrystallised from 50% aqueousethanol, and then from ethanol, to give 5- benzyloxy 2 methoxybenzoicacid (8 g.), mp. 114- 116 C.

The 2-methoxy-S-trifluoromethylbenzonitrile used as a starting materialin the above preparation was prepared as follows:

2-Bromo 5 trifluoromethylbenzonitrile (2.5 g.; prepared as described byM. Gordon, I. J. Pachter and J. W. Wilson, Arzneimittel-Forsch., 1963,13, 802) and a solution of sodium methoxide (prepared from 0.5 g. sodiumand 20 ml. anhydrous methanol) were stirred and refluxed together for 4hours, and allowed to stand at room temperature overnight. The methanolwas evaporated and the residue was acidified with 2N hydrochloric acid,with cooling. The mixture was extracted with diethyl ether, and theextract was dried over anhydrous sodium sulphate, filtered and thefiltrate was evaporated, and the residue was recrystallised from pentaneto give 2-methoxy-5-trifluoromethylbenzonitrile (1.0 g.), m.p. 31-33 C.

EXAMPLE 2 8-Aza-2-phenylpurin-6-one (3 g., prepared as described inExample 1) was added in portions to a stirred mixture of concentratednitric acid (density 1.42, 5 ml.) and concentrated sulphuric acid (6ml.), maintaining the temperature at 20-30 C. Stirring was continued fora further 1 hour. The mixture was left to stand overnight and thenpoured into ice-water (50 ml.). The precipitated solid was filtered offand recrystallised from aqueous dimethylformamide to give8-aza-2-(3-nitrophenyl)purin-6-one monohydrate (0.8 g.), in the form ofa pale yellow solid, mp. 160165 C.

By proceeding in a similar manner, but substituting 8- aza-2-(2-methoxyphenyl)purin 6 one (prepared as described in Example 1) and8-aza-2-(2-hydroxyphenyl)- purin-6-one (prepared as described in Example3) for the 8-aza-2-phenylpurin-6-one used as a starting material in theabove preparation, there were prepared8-aza-2-(2-methoxy-5-nitrophenyl)purin-6-one, m.p. 260261 C. (withdecomposition) and 8-aza-2-(2-hydroxy 3,5 dinitrophenyl)purin-6-one,characterised in the form of its ammonium salt Which decomposed withoutmelting at 315 C.

a4- EXAMPLE 3 A solution of 8-aza-2-(2-benzyloxyphenyl)purin-6-one (1.0g.; prepared as described in Example 1) in methanol (100 ml.) containing5% palladium-charcoal (0.2 g.) was hydrogenated at atmospheric pressureand room temperature. The theoretical volume (71 ml.) of hydrogen wastaken up during 75 minutes. The solid was filtered off and the filtratewas evaporated to give crude product (0.25 g.). The catalyst which wasfiltered ofl. was extracted with 2N sodium hydroxide solution and theextract was filtered and acidified with 2N hydrochloric acid to give afurther quantity (0.4 g.) of crude product. The combined crude productswere recrystallised from aqueous ethanol to give8-aza-2-(Z-hydroxyphenyl)purin-6- one (0.4 g.), mp. 283-284" C. (withdecomposition).

By proceeding in a similar manner but substituting 8-aza-2-(S-benzyloxy-Z-methoxyphenyl)purin-6-one and 8- aza- 2(2,5-dibenzyloxyphenyl)purin-6-one for the 8- aza 2(2-benzyloxyphenyl)purin-6-one used as a starting material in the abovepreparation, there were prepared 8aza-Z-(5-hydroxy-2-methoxyphenyl)purin-6-one, m.p. 288.5290 C. (withdecomposition) and 8-aza-2- [2(or 5)-benzyloxy-5(or2)-hydroxyphenyl]purin-6-one, mp. 268-272 C. (with decomposition),respectively.

EXAMPLE 4 8-Aza-2-(Z-methoxyphenyl)purin-6-one (200 mg; prepared asdescribed in Example 1) was dissolved in a 2N aqueous solution of sodiumhydroxide (4 m1.), and the stirred solution treated dropwise withglacial acetic acid. While the pH was still above 11, a cream-colouredsolid was precipitated. This was filtered off, recrystallised from amixture of ethanol and diethyl ether, and left to dry in air overnightto give the sodium salt of 8-aza-2-(2-methoxyphenyl)purin-6-one as acrystalline hydrate 100 mg), each mole of the salt being associated with2.4 moles of water, melting with decomposition over the range 50- 250 C.

EXAMPLE 5 A solution of potassium hydroxide pellets (0.33 g.) in drymethanol (13 ml.) was added to a hot solution of choline chloride (0.7g.) in isopropanol (36 ml.). The mixture was cooled to 0 C., and thepotassium chloride filtered off and rinsed with isopropanol (2X 3 ml.).8-Aza-2-(2-methoxyphenyl)purin 6 one (1.13 g.; prepared as described inExample 1) was added to the combined filtrate and washings and themixture warmed for 4 minutes on the steam-bath. The warm mixture wasfiltered and diluted with dry diethyl ether ml.). The gum whichseparated out crystallised on standing at 0 C. overnight, and thecrystals so formed were filtered off, rinsed with dry diethyl ether,recrystallised from a mixture of dry ethanol and diethyl ether, anddried to give the choline salt of 8-aza-2-(2-methoxyphenyl)purin-6-onein the form of its hemihydrate (1.2 g.), m.p. 158160 C.

EXAMPLE 6 8 Aza-Z-(Z-methoxyphenyl)purin-6-one (2.4 g.) was refluxed for5 minutes with a solution of sodium (0.23 g.) in anhydrous ethanol (25ml.), and cooled. Anhydrous diethyl ether (75 ml.) was added, and thesolid was filtered ofl, and recrystallised from a mixture of anhydrousethanol and anhydrous diethyl ether to give the sodium salt of 8aza-2-(3-methoxyphenyl)purin-6-one hemihydrate (0.75 g.), m.p. ca 310 C.(with decomposi- EXAMPLE 7 A mixture of 8aza-2-(Z-methoxyphenyl)purin-6-one (237 g.), triethanolamine (400 ml.)and anhydrous ethanol (3 litres) was refluxed for 1 hour. The solutionwas filtered and left to stand at 0 C. for 2 hours. The solid whichseparated was filtered ofl and recrystallised from anhydrous ethanol togive the triethanolamine salt of 8- aza-2-(Z-methoxyphenyl)purin-6-one,m.p. 138-139 C., (216 g.).

By proceeding in a similar manner, but substituting diethylamine andtriethylamine for the triethanolamine used as a starting material in theabove preparation, there were prepared the diethylamine salt of8-aza-2-(2-methoxyphenyl)purin-6-one (which contained 0.4 moles of waterof crystallisation), m.p. 138-142 C., and the triethylamine salt of 8aza-2-(Z-methoxyphenyl)purin-6-one, m.p. 184-197 C., respectively.

EXAMPLE 8 A mixture of 8 aza-2-(2-methoxyphenyl)purin-6-one (4.0 g.),diethanolamine (4 ml.) and anhydrous ethanol (40 ml.) was refluxed for 5minutes, concentrated to half its volume and diluted with anhydrousdiethyl ether (60 ml.). The solid which separated was recrystallisedfrom anhydrous ethanol (55 ml.) to give the diethanolamine salt of8-aza-2-(2-methoxyphenyl)purin-6-one, m.p. 142- 143 C., (3.4 g).

By proceeding in a similar manner, but substituting ethylenediamine andoctadecylamine for the diethanolamine used as a starting material in theabove preparation, there were prepared the ethylenediamine salt of 8-aza-2-(2-methoxyphenyl)purin-'6 one (which contained 0.25 moles of Waterof crystallisation), m.p. 208-209 C. (with decomposition), and theoctadecylamine salt of 8- aza-2-(Z-methoxyphenyl)purin-fi-one, m.p.97-98 C., respectively.

EXAMPLE 9' 1-(3,4-Dihydroxyphenyl)-2-isopropylaminoethanol sulphate(1.15 g.) was refluxed for 5 minutes with a solution of sodium (0.1 g.)in anhydrous ethanol (10 ml.). The sodium sulphate was filtered off, and8-aza-2-(2-methoxyphenyl)purin-6-one (1.0 g.) was added to the filtrate,and the mixture was refluxed for 5 minutes. The mixture was filtered,and the filtrate was diluted with anhydrous diethyl ether, and the solidwhich separated was filtered olf and recrystallised from isopropanol togive the 1-(3,4- dihydroxyphenyl)-2-isopropylaminoethanol salt of 8-aza-2-(2-methoxyphenyl)purin-6-one (which contained 0.33 moles of water ofcrystallisation), m.p. 155 C. (with decomposition) after softening at ca105 C., (0.35 g.).

EXAMPLE 10 Toluene-p-sulphonic acid monohydrate (1.04 g.) was heated inrefluxing xylene (80 ml.) for 3.5 hours, using a Dean and Starkapparatus, in order to remove water. 5-Amino-4-carbamoyl-lH-1,2,3triazole (1.52 g.) was then added, followed by triethyltrithioorthobenzoate (3 ml.). Refluxing was continued for a further 5.5hours. The cooled reaction mixture was extracted with 2N aqueous sodiumhydroxide solution, and the aqueous layer separated and acidified withaqueous hydrochloric acid. A dark brown solid (0.9 g.) separated, whichwas filtered oif and extracted with boiling isopropanol. Upon coolingthe isopropanol extract, light brown crystals were obtained, which upona further recrystallisation from isopropanol with the use of adsorbentcharcoal, gave 8-aza- 2-phenyl-purin-6-one (0.12 g.) as buff-colouredcrystals, m.p. 278 C. (with decomposition).

The 5-amino-4-carbamoyl-1H-1,2,3,-triazole, used as a starting materialin the above preparation, may be prepared according to the methoddescribed by J. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956,78, 5832.

Triethyl trithioorthobenzoate may be prepared according to the methoddescribed by L. C. Rinzema, J. Stotfelsma, and J. F. Arens, Rec. Trav.Chim., 1959, 78, 354.

EXAMPLE 11 5-Amino-4-carbamoy1-lH-1,2,3 triazole (0.7 g.), triethyltrithioorthobenzoate (1.5 ml.) and boron trifluoride etherate (0.38 ml.)were heated together overnight in refluxing anhydrous xylene (25 ml.).The cooled reaction mixture was extracted with 2N aqueous sodiumhydroxide solution. The aqueous layer was separated, treated withadsorbent charcoal, and warmed. The charcoal was then filtered ofl, andthe filtrate acidified with aqueous hydrochloric acid, whereupon 8aza-2-phenylpurin-6-one (0.2 g.), m.p. 273 C. (with decomposition), wasprecipitated.

EXAMPLE 12 5-Amino-4-carbamoyl-1H-1,2,3 triazole (0.8 g.), benzamidinehydrochloride (1.0 g.) and anhydrous sodium acetate (1.2 g.) were heatedtogether at 190 C. for 24 hours. The cooled reaction mixture was treatedwith 2N aqueous lithium hydroxide solution (20 ml.), and the undissolvedsolid was filtered olf. The filtrate was adjusted to pH 4 Withconcentrated hydrochloric acid, and was then left to stand at 0 C. for 2hours. The precipitated solid (0.46 g.) was filtered ofl, washed withwater, and recrystallised from ethanol to give 8-aza-2-phenylpurin-6-one (0.17 g.), m.p. 283 C. (with decomposition).

EXAMPLE 13 Sodium nitrite (3 g.) was added slowly with stirring to asolution of concentrated hydrochloric acid ml.) in water (100 ml.)maintained at between 5 and 0 C. by means of an ice-salt bath.2-(2-Allyloxyphenyl)-4,5- diaminopyrimid-6-one (5.1 g.) was then addedin portions during 30 minutes with sgatrtirin filan0urh2,g during 30minutes with stirring at between -5 and 0 C. The cooling bath wasremoved, and the mixture stirred at room temperature overnight. Thesolid which separated was filtered 01f and dissolved in a solution ofconcentrated ammonium hydroxide (10 ml.) in water (100 ml.). Thesolution was heated with charcoal, filtered, and the filtrate acidifiedwith glacial acetic acid. The solid which separated was filtered off andrecrystallised from methanol to give2-(2-allyloxyphenyl)-8-azapurin-6-one (1.7 g.), m.p. 173-175 C.

By proceeding in a similar manner, but substituting 4,5- diamino 2(2-methoxy-3-methylphenyl)pyrimid-6-one, crude 4,5 diamino2-(2-methoxy-5-methylphenyl)pyrimid-6-one, 4,5diamino-2-(2-methoxy-3,S-dimethylphenyl)pyrimid 6 one, crude4,5-diarnino-2-(5-tert-butyl-2- methoxyphenyl)pyrimid 6 one and4,5-diamino-2-(4- benzylphenyl)pyrimid-6-one for the 2-(2-allyloxyphenyl)- 4,5-diaminopyrimid-6-one used as a starting materialin the above preparation, there were prepared 8-aza-2-(2-methoxy-3-methylphenyl)purin-fi-one, m.p. 248-249 C. (withdecomposition), 8-aza-2-(2-methoxy-5-methylphenyl)purin-6-one, m.p.230-232 C. (with decomposition),8-aza-2-(2-methoxy-3,S-dimethylphenyl)purin-6-one, m.p. 223-224" C.(with decomposition), 8-aza-2-(5-tert-butyl-Z-methoxyphenyl)purin-6-one, m.p. 260262 C. (with decomposition) and 8aza-2-(4-benzylphenyl)purin-6- one, m.p. 272-274 C. (withdecomposition), respectively.

The 2 (2 allyloxyphenyl)-4,5-diaminopyrimid-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

2 (2 Allyloxyphenyl) -4- amino-S-nitrosopyrirnid-6- one (6.3 g.) wassuspended in a solution of triethylamine (15 ml.) in water (250 ml.).Sodium dithionite (12 g.) was added in portions with stirring at roomtemperature. The temperature of the mixture was then raised to 60 C.,and it was stirred at this temperature for a further 20 minutes. The pHof the mixture was adjusted to 7 by the addition of glacial acetic acid,and the mixture cooled in ice/ water. The solid was filtered off andwashed with water to give 2 (2 allyloxyphenyl) 4,5 diaminopyrimid-6- one(5.1 g.), m.p. 127-l30 C.

By proceeding in a similar manner, but substituting 4 amino 2 (2methoxy-3-methylphenyl)-5-nitrosopyrimid 6 one, 4 amino 2(2-methoxy-5-methylphenyl) 5 nitrosopyrimid-6-one, 4-amino-2-(2-methoxy-3,5-dimethylphenyl)-5-nitrosopyrimid-6-one, 4 amino-2- tert butyl 2methoxyphenyl)-5-nitrosopyrimid 6-one and4-amino-2-(4-benzylphenyl)-5-nitrosopyrimid- 6-one for the 2 (2allyloxyphenyl)-4-an1ino-5-nitrosopyrimid 6 one used as a startingmaterial in the above preparation, there were prepared4,5-diamino-2-(2-methoxy 3 methylphenyl)pyrimid-fi-one, mp. 248-249" C.(with decomposition), crude 4,5-diamino-2-(2-methoxy- 5methylphenyl)pyrimid 6 one [characterised as its hydrochloride, mp.260-262 C. (with decomposition), which contained 0.1 moles of water ofcrystallisation per mole], 4,5 diamino 2 (2 methoxy 3,5dimethylphenyl)pyrimid-6-one, m.p. 168-170 C., crude 4,5-diamino 2 (5tert butyl-2-methoxyphenyl)pyrimid-6- one, m.p. 85-9l C., and4,5diamino-2-(4-benzylphenyl) pyrimid-6-one, mp. 205-208" C.,respectively.

The 2 (2 allyloxyphenyl) 4 amino-S-nitrosopyrimid-6-one, used as astarting material in the above preparation, was prepared as follows:

2-Allyloxybenzamidine hydrochloride (10.2 g.) was added to a solution ofsodium (4.6 g.) in anhydrous methanol (200 ml.) with stirring, followedby ethyl aoximinocyanoacetate (7.6 g.), and the mixture was stirredunder reflux for 6 hours. The hot mixture was poured into water (500ml.) and acidified with glacial acetic acid. The blue solid was filteredolf, washed with water and recrystallised from 50% aqueous acetic acidto give 2 (2 allyloxyphenyl) 4 amino 5 nitrosopyrimid-6-one (7.3 g.),m.p. 217-220 C.

By proceeding in a similar manner, but substituting 2- methoxy 3methylbenzamidine hydrochloride, 2-methoxy-S-methylbenzamidinehydrochloride, crude 2-rnethoxy-3,5-dimethylbenzamidine, S-terr-butyl 2methoxy benzamidine hydrochloride and 4-benzylbenzamidine hydrochloridefor the 2-allyloxybenzamidine hydrochloride used as starting material inthe above preparation, there were prepared 4 amino2-(2-methoxy-3-methylphenyl)-5-nitrosopyrimid-6-one, m.p. 224 C. (withdecomposition), 4 amino 2 (2 methoxy 5methylphenyl)-5-nitrosopyrimid-6-one, m.p.224 C. (with de composition),4 amino 2 (2-methoxy-3,5-dimethylphenyl) 5 nitrosopyrimid 6 one, m.p.212 C. (with decomposition), 4 amino 2 (5-tert-butyl-Z-methoxyphenyl) 5nitrosopyrimid 6 one, mp. 215-218 C. (with decomposition), and4-amino-2-(4-benzylphenyl)- 5 nitrosopyrimid 6 one, m.p. 237239 C. (withdecomposition), respectively.

The 2-allyloxybenzamidine hydrochloride, used as a starting material inthe above preparation, was prepared as follows:

2-Allyloxybenzamide (20 g.; prepared as described by J. A. Faust, L. H.Jules and M. Sahyun, J. Amer. Pharm. Assoc., 1956, 45, 514) wasdissolved in anhydrous methylene chloride (250 ml.). Methylfiuorosulphonate (16 g.) Was added and the mixture was stirred at roomtemperature for 2 hours, and then left to stand overnight. The solventwas evaporated in vacuo and the residue was mixed with ethanolic ammoniasolution (200 ml.; prepared by saturation of anhydrous ethanol withammonia gas at 0 C.) and the mixture was stirred for 1 day and left tostand at room temperature for a further 1 day. The mixture wasevaporated to dryness, and the residue was mixed with chloroform (300ml.) and water (200 ml.). The mixture was cooled to about 8 C. andstirred vigorously while 50% aqueous sodium hydroxide solution was addeddropwise until pH 11 was attained. The chloroform layer was separated,washed once with icecold water, and dried over sodium sulphate. Thedried chloroform solution was evaporated in vacua, and the residue wasdissolved in anhydrous diethyl ether, and the solution treated with anexcess of an anhydrous solution of hydrogen chloride in diethyl ether.The solid which separated was filtered off to give 2-allyloxybenzamidinehydrochloride (19.08 g.), mp. 166-175 C.

The 2 methoxy 3 methylbenzamidine hydrochloride, used as a startingmaterial in the above preparation, was prepared as follows:

A solution of triethyloxonium borofluoride (23 g.) in anhydrousmethylene chloride (60 ml.) was added to a solution of2-methoxy-3-methylbenzarnide [19.7 g.; prepared as described in FrenchPatent M. 21] in anhydrous methylene chloride (200 ml.). The mixture waskept at room temperature for 3 days, concentrated to about ml. anddiluted with anhydrous diethyl ether (300 ml.). The solid whichseparated was filtered off and washed with anhydrous diethyl ether togive ethyl 2-methoxy-3-methylbenzimidate borofluoride (28.7 g.), m.p.93-96 C., which was pure enough for use in the next stage of thesynthesis. An aliquot was recrystallised from a mixture of anhydrousmethylene chloride and anhydrous diethyl ether to give pure ethyl2-methoxy-3-methylbenzimidate borofluoride, mp. 102-104" C.

Ethyl 2 methoxy 3 methylbenzimidate borofluoride (28 g.) was mixed witha saturated anhydrous solution of ammonia in ethanol (46 ml.), themixture was kept at room temperature in a stoppered vessel for 3 daysand then evaporated to dryness in vacuo. The residue was dissolved inwater (25 ml.) and treated with 5N sodium hydroxide solution (50 ml.).The solution was saturated with sodium chloride and extracted withdiethyl ether. The extract was dried over potassium hydroxide andevaporated to give crude 2-methoxy-3-methylbenzamidine, m.p. 72-74 C.This was dissolved in anhydrous ethanol (40 ml.) and the solutiontreated with a saturated anhydrous solution of hydrogen chloride indiethyl ether (100 ml.), and diluted with anhydrous diethyl ether (100ml.) The solid which separated was filtered off and washed withanhydrous diethyl ether to give 2-methoxy-3-methylbenzamidinehydrochloride (17.8 g.), m.p. 208-209 C. (with decomposition).

By proceeding in a similar manner, but substituting 2-methoxy-S-methylbenzamide (prepared as described by L. Gattermann,Liebigs Annalen der Chemie, 1888, 244, 66) and2-methoxy-3,S-dimethylbenzamide for the 2-methoxy- 3-methylbenzamideused as a starting material in the above preparation, there wereprepared ethyl 2-methoxy- S-methylbenzimidate borofluoride, M.P. 202-204C. (with decomposition), Z-methoxy 5 methylbenzamidine hydrochloride,m.p. 226-227 C. (with decomposition), crude ethyl2-methoxy-3,S-dimethylbenzimidate borofluoride and crude2-methoxy-3,S-dimethylbenzamidine.

The 2-methoxy-3,S-dimethylbenzamide, used as a starting material in theabove preparation, was prepared as follows:

2 Methoxy 3,5 dimethylbenzoic acid (52.7 g.) and thionyl chloride (200ml.) were refluxed together for 1 hour. The excess of thionyl chloridewas evaporated in vacuo and the residue dissolved in anhydrous diethylether (100 ml.). The solution was added dropwise to stirred, ice-cooled,concentrated aqueous ammonia solution (350 ml.) during 50 minutes, andthe mixture was stirred for a further 3 hours and left at roomtemperature overnight. The solid obtained was filtered off, washed withdiethyl ether and recrystallised from ethanol (with the use of charcoal)to give 2-methoxy-3,S-dimethylbenzamide (27.8 g.), m.p. 109113 C., whichwas pure enough for use in the next stage of the synthesis. An aliquotwas further recrystallised from ethanol to give 2-methoxy-3,S-dimethylbenzamide, m.p. 114-116 C.

The Z-methoxy-3,5-dimethylbenzoic acid, used as a starting material inthe above preparation, was prepared as follows:

The disodium salt of 2-hydroxy-3,S-dimethylbenzoic acid (21 g.) anddimethyl sulphate (92 ml.) were stirred together at -150 C. for 2.5hours. After standing overnight, the mixture was added to a solution ofsodium hydroxide (40 g.) in water (250 ml.), and the mixture stirred andheated on the steam-bath for 1 hour. Charcoal was added, the mixture wasfiltered and the filtrate was cooled, acidified with concentratedhydrochloric acid, and maintained at C. The solid which separated wasfiltered off and recrystallised from aqueous ethanol to give 2-methoxy-3,S-dimethylbenzoic acid (14.7 g.), mp. 97- 98 C.

The disodium salt of 2-hydroxy-3,S-dimethylbenzoic acid, used as'astarting material in the above preparation, was prepared as follows:

2- Hydroxy-3,S-dimethylbenzoic acid (20 g.; prepared as described by W.R. Nummy and D. S. Tarbell, J. Amer. Chem. Soc., 1951, 73, 1500) wasadded to a solution of sodium (5.5 g.) in anhydrous methanol (200 ml.).Anhydrous toluene (200 ml.) was added and most of the excess of methanolwas distilled off. The solid which separated was filtered olf and washedwith anhydrous diethyl ether to give the disodium salt of2-hydroxy-3,S-dirnethylbenzoic acid (22.8 g.).

The -tert-butyl-2-methoxybenzamidine hydrochloride, used as a startingmaterial in the above preparation, was prepared as follows:

5-tert-Butyl-Z-methoxybenzamidoxime (22.2 g.) was dissolved in ethanol(250 ml.) and hydrogenated at 5.6 kg./cm. pressure in the presence ofRaney nickel (4.5 g.) until the theoretical quantity of hydrogen hadbeen absorbed (16.25 hours). The catalyst was filtered ofi and thefiltrate evaporated to dryness in vacuo. The residue was dissolved inthe minimum quantity of anhydrous ethanol, an, excess'of an anhydroussolution of hydrogen chloride in diethyl ether was added and the mixturewas chilled. The solid which separated was filtered ofl and Washed withanhydrous diethyl ether to give 5-tert-butyl-2-methoxybenzamidinehydrochloride (22.9 g.), mp. 180- ,The5-tert-butyI-Z-methoxybenzarnidoxirne, used as a starting material inthe above preparation, was prepared as 'follows;

Sodium carbonate (57 g.) was added with stirring to a mixture ofhydroxylamine hydrochloride (75 g.), S-tertbu'ty1-2-methoxybenzonitrile(50 g.) and water (400 ml.). Ethanol '(400 ml.) was added, and themixture was stirred at room temperature for 45 minutes and then heatedunder reflux for 18 hours. The ethanol was evaporated in vacuo, and thecooled aqueous suspension was extracted three times with diethyl ether.The combined extracts were dried over magnesium sulphate, filtered, andevaporated. The residual glass was triturated with warm diethyl ether,and the solid obtained was filtered off, washed with diethyl ether, andrecrystallised from benzene to give 5-tert-buty1-2-methoxybenzamidoxime(48 g.), m.p. 132-133 C.

' The 5-tert-butyl-2-methoxybenzonitrile, used as a starting material inthe above preparation, was prepared as follows:

5-tart Butyl-2-hydroxybenzonitrile (50 g.; prepared as described by F.B. Dains and I. R. Rothrock, J. Amer. Chem'., 1894, 16, 635) was addedto a solution of sodium (7.43 g.) in anhydrous ethanol (150 ml.),followed by methyl iodide (50 ml.). The mixture was refluxed for 3hours, during which time a further quantity of methyl iodide (20 ml.)was added in portions. The mixture was evaporated in vacuo, and theresidue treated with water (500 ml.). The oil obtained was extractedwith diethyl ether, and the aqueous layer further extracted twice withdiethyl ether. The combined extracts were dried and evaporated, and theresidual oil was distilled in vacuo to give5-zert-butyl-Z-methoxybenzonitrile (50.3 g.), b.p. 138-140 C./ 0.2 mm.Hg.

' The 4-benzylbenzamidine hydrochloride, used as a starting material inthe above preparation, was prepared as followsi v 4-Benzylbenzonitrile(8.7 g.; prepared as described by N. Moses, Ben, 1900, 33, 2623) wasdissolved in anhydrous chloroform (50 ml.) and anhydrous ethanol ml.),and the solution was saturated at 0 C. with anhydrous hydrogen chloride,and then kept at 0 C. for 3 days. The solvent was removed in vacuo andthe residue was triturated with anhydrous diethyl ether. The solid (7g.) was filtered off and dissolved in saturated anhydrous ethanolicammonia solution (33 ml.). The solution was kept at 0 C. for 3 days, andevaporated to dryness. The residue was recrystallised from water to give4- benzylbenzamidine hydrochloride (1.4 g.), mp. 215- 217 C.

EXAMPLE 14 A solution of 2-(Z-methoxy-S-nitrophenyl)-8-azapurin- 6-one(1.87 g.) (prepared as described in Example 2) in Z-ethoxyethanol (50ml.) was shaken at room temperature with a platinum oxide catalyst (0.12g.) under hydrogen (5 kg./cm. After the uptake of hydrogen was complete,the filtered solution was concentrated to dryness and the brown residualsolid was recrystallised from aqueous N,N-dimethylformamide. A portionof this material was further purified by dissolution in 2N ammoniumhydroxide solution followed by acidification of the filtered solutionwith 2N acetic acid. The brown precipitate was filtered, washed wellwith water and dried to give 2-(5- amino-2-methoxyphenyl)-8-azapurin 6one hcmihydrate (0.2 g.) in the form of a brown solid, M.P. 204-206" C.(with decomposition, sintering at about 175 C.).

EXAMPLE 15 Sodium nitrite (1.8 g.) was added to a solution ofconcentrated hydrochloric acid (15.5 ml.) in water (15.5 ml.) at 0 C.The solution was stirred at 0 C'. while 4,5-diamino-2-benzylpyrimid-6-one (2.8 g.) was added in portions during 30minutes. The cooling bath was removed, and the mixture was stirred atroom temperature for a further 2 hours, and then allowed to stand for 3hours. The solid was filtered ofl, washed with water, and suspended inwater (25 ml.). Concentrated aqueous ammonia was added dropwise untilmost of the solid dissolved. A trace of insoluble solid was removed byfiltration, and the filtrate was acidified with glacial acetic acid. Theprecipitated solid was filtered off and washed with water to give8-aza-2-benzylpurin-6-one hydrate (2.35 g.) in the form of an off-whitesolid (melting at C., solidifying and remelting at 220 C. withdecomposition). Recrystallisation from water followed by heating thesolid in vacuo at C. gave anhydrous 8-aza-2-benzylpurin-6-one (0.55 g.),m.p. 236 C. (with decomposition).

The 4,S-diamino-Z-benzylpyrimid-6-one, used as a starting material, wasprepared by either of the following procedures:

(a) A solution of sodium dithionite ('62 g.) in water (300 ml.) wasadded dropwise during 30 minutes to a solution of4-amino-Z-benzyl5-phenylazopyrimid--one (27 g.) in dimethylformamide(1000 ml.) at 75 C. The mixture was cooled, and the insoluble solid wasfiltered off. The filtrate was evaporated in vacuo, the residue wasstirred with water, and the solid filtered off. This solid was extractedwith boiling water (250 ml.), the extract was filtered hot and thencooled. The solid which separated was recrystallised from water to give4,5-diamino- 2-benzylpyrimid-6-one (12.4 g.) in the form of oil-whiteneedles, mp. 243 C. (with decomposition).

(b) Sodium dithionite (30 g.) was added in portions to an agitatedsuspension of 4-amino-2-benzyl-S-phenylazopyrimid-G-one (14 g.) in amixture of ethanol (200 ml.) and 2N aqueous sodium hydroxide solution(200 ml.) maintained at a temperature near to the reflux temperature.The mixture was then heated under reflux for 20 minutes, treated with afurther quantity of sodium dithionite (20 g.) and the mixture heatedunder reflux for a further 30 minutes. The mixture was then evaporatedto dryness, the residue was dissolved in water (200 ml.), acidified topH 6 by means of concentrated hydrochloric acid, cooled to 0 C., andfiltered. The solid thus obtained was recrystallised from water to give4,5-diamino-2-benzylpyrimid-6-one (4.4 g.), m.p. 243-246 C.

The 4-amino-2-benzyl-5-phenylazopyrimid-6-one, used as a startingmaterial in the above preparations, was prepared as follows:

A cold solution of benzenediazonium chloride (prepared by the methodwell known in the art, from 2 g. aniline) was added dropwise withstirring to a solution of 4-amino-2-benzylpyrimid-6-one (4 g.) andsodium hydroxide (1.6 g.) in water (50 ml.) at 5 C. After stirring for afurther 1 hour, the solid was filtered off and recrystallised from amixture of dimethylformamide and water (4:1 v./v.) to give4-amino-2-benzyl-S-phenylazopyrimid- 6-one (3.8 g.) in the form oforange needles, which decomposed at 256-257 C.

The 4-amino-2-benzylpyrimid-6-one was prepared according to the methoddescribed by J. Brock. Z. Chem., 1968, 8, 143.

EXAMPLE 16 Sodium nitrite (0.95 g.) was added slowly with stirring to asolution of concentrated hydrochloric acid (20 ml.) in water (20 ml.)maintained at 5 C. 4,5-diamino-2- (2-phenylethyl)pyrimid-6-one (1.58 g.)was then added during 5 minutes, maintaining the mixture at 5 C., andstirring at 5 C. was continued for a further 15 minutes. A furtherportion of sodium nitrite (0.95 g.) was then added, stirring at 5 C. wascontinued for a further 20 minutes, and the mixture was then maintainedat room temperature overnight. The solid which separated was filteredoff, washed with a small volume of water, and dissolved in diluteaqueous ammonia. The solution was filtered and acidified to pH 4 withglacial acetic acid. The solid obtained (1.36 g.), m.p. 267-269 C. (withdecomposition) was recrystallised from aqueous dimethylformamide anddried at 100 C./0.2 mm. Hg pressure over silica gel to give8-aza-2-(Z-phenylethyl)purin-6-one (0.82 g.), m.p. 275-277 C. (withdecomposition).

By proceeding in a similar manner, but substituting 4,5-diarnino-Z-(3-phenylpropyl)pyrimid-fi-one for the4,5-diamino-Z-(2-phenylethyl)pyrimid-6-one used as a starting materialin the above preparation, there was prepared8-aza-2-(3-phenylpropyl)purin-6-one, m.p. 197199 C. (with decomposition)(containing 0.1 mole of ethanol of crystallisation).

The 4,5-diamino-2-(2-phenylethyl)pyrimid-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

Crude sodium salt of 4-amino-5-nitroso-2-(2-phenylethyl) pyrimid-6-one(3.8 g.) was dissolved in water (5.5 ml.). A trace of insoluble materialwas filtered off, and sodium dithionite (4.08 g.) was added slowly tothe filtrate with stirring. The solid which separated was filtered off,washed with water, and recrystallised from ethanol to give4,5-diamino-2-(2-phenylethyl)pyrimid-fi-one (0.75 g.), m.p. 204-206 C.(with decomposition).

By proceeding in a similar manner, but substituting a solution of4-amino-5-nitroso-2-(3-phenylpropyl)pyrimid- 6-one in aqueous sodiumhydroxide for the aqueous solution of the crude sodium salt of4-amino-5-nitroso-2-(2- phenylethyl)pyrimid-6-one used in the abovepreparation, there was prepared crude 4,5-diamino-2-(3-phenylpropyl)pyrimid-6-one.

The sodium salt of 4-amino-5-nitroso-2-(2-phenylethyl)pyrimid-6-one,used as a starting material in the above preparation, was prepared asfollows:

3-Phenylpropionamidine hydrochloride (4.33 g.; prepared as described byP. W. Neber and A. Uber, Leibigs Annalen der Chemie, 1928, 467, 52) wasadded to a solution of sodium methoxide (prepared from 2.17 g. sodiumand 37 ml. anhydrous methanol). Ethyl a-oximinocyanoacetate (3.34 g.)was added, and the mixture was refluxed with stirring for 5.25 hours andleft to stand overnight. The mauve solid was filtered off and washedwith a small quantity of anhydrous methanol to give the crude sodium 32salt of 4-amino-5-nitroso-2-(2-phenylethyl)pyrimid-6one (3.9 g.). Analiquot was dissolved in water, and the solution was filtered andacidified to pH 4 with glacial acetic acid to give4-amino-5-nitroso-2-(2-phenylethyl)pyrimid- 6-one as a turquoise solid,m.p. 253 C. (with decomposition, sintering at 188 C.).

By proceeding in a similar manner, but substituting 4-phenylbutyramidinehydrochloride for the 3-phenylpropionamidine hydrochloride used as astarting material in the above preparation, there was prepared 4-amino-5-nitroso-2-3-phenylpropyl)pyrimid 6 one, m.p. 166167 C. (withdecomposition).

The 4-phenylbutyramidine hydrochloride, used as a starting material inthe above preparation, was prepared as follows:

A solution of 4-phenylbutyronitrile (5 g.; prepared as described by H.Rupe, Liebigs Annalen der Chemie, 1913, 395, 118) and anhydrous ethanol(5 ml.) in anhydrous chloroform (50 ml.) was cooled in an ice/salt bathand saturated with anhydrous hydrogen chloride. The mixture was allowedto stand at room temperature for 8 days and diluted with anhydrousdiethyl ether (250 ml.). The ethyl 4-phenylbutyrimidate hydrochloride(6.44 g.), m.p. 88.5 C. (with decomposition), which separated, wasfiltered off, and treated with anhydrous saturated ethanolic ammonia (65ml.), and the mixture kept at room temperature for 2 days. The solutionwas concentrated to small volume and diluted with anhydrous diethylether (200 ml.). The solid obtained was filtered off, and recrystallisedfirstly from a mixture of ethanol and diethyl ether, and then from amixture of isopropanol and diethyl ether to give 4-phenylbutyramidinehydrochloride (3.2 g.), m.p. -157 C.

EXAMPLE 17 4,5-Diamino-2-isopropylpyrimid-6-one (2.4 g.) was dissolvedwith heating in a mixture of concentrated hydrochloric acid (50 ml.) andwater (50 ml.), the solution was filtered hot and the filtrateevaporated to dryness. The residue was dissolved in warm water, thesolution cooled below 19 C., and sodium nitrite (1.55 g.) added slowlyin portions. The mixture was stirred for one hour at below 10 C., thenleft to stand at 0 C. overnight. The solid product was filtered off andthe liquors extracted with ethyl acetate to give further product. Thecombined products were crystallised from water to give8-aza-2-isopropylpurin-6-one (0.79 g.), m.p. 250255 C. (withdecomposition). A further quantity of 8-aza-2- isopropylpurin-G-one(0.43 g.), m.p. 255-256'C. (with decomposition), was obtained from theaqueous recrystallisation liquors.

By proceeding in a similar manner, but substituting4,S-diamino-2-isobutylpyrimid-6-one for the 4,5-diamino-2-isopropylpyrimid-6-one used as a starting material in the abovepreparation, there was prepared 8-aza-2-isobutylpurin-6-one, m.p.225-230 C.

The 4,S-diamino-2-isopropylpyrimid-6-one, used as a starting material inthe above preparation, was prepared as follows:

Sodium dithionite (21 g.) was added in portions to an agitatedsuspension of 4-amino-2-isopropyl-5-phenylazopyrimid-6-one (8.3 g.) in amixture of ethanol (140 ml.) and water (140 ml.) maintained at atemperature near to the reflux temperature. The mixture was then heatedunder reflux for 1 hour, left to stand at 0 C., overnight, and filteredto give crude 4,5-diamino-Z-isopropylpyrimid- 6-one (2.75 g.), m.p.ZOO-220 C. The liquors were continuously extracted with methylenechloride for 48 hours, the extract dried over magnesium sulphate andevaporated to dryness to give a further quantity of the crude product(2.1 g.), m.p. -195 C. The combined products were pure enough for use inthe next stage.

An aliquot (0.5 g.) recrystallised from methanol gave pure4,5-diamino-2-isopropylpyrimid-6-one, (0.23' g.), m.p. 220-225 C.

By proceeding in a similar manner, but substituting4-amino-2-isobutyl-S-phenylazopyrimid-6-one for the 4amino-2-isopropyl-5-phenylazopyrimid-6-one used as a starting materialin the above preparation, there was prepared4,5-diamino-2-isobutylpyrimid-6-one, m.p. 198- 200 C. (recrystallisedfrom water).

The 4-amino-2-isopropyl-S-phenylazopyrimid 6 one, used as a startingmaterial in the above preparation, was prepared as follows:

A cold solution of benzenediazonium chloride [prepared, by the methodwell known in the art, from 13.3 g. aniline in a 1:1 v./v. mixture ofwater and concentrated hydrochloric acid (120 ml.)] was added dropwisewith stirring to a solution of 4-amino-2-isopropylpyrimid-6- one (28 g.)and sodium hydroxide (14.8 g.) in water 450 ml.) at 5 C. After stirringfor a further 1 hour, the mixture was filtered. The filtrate wasadjusted to pH 6 by the addition of aqueous sodium hydroxide solution,and the resultant solid was isolated to give crude4-amino-2-isopropyl-S-phenylazopyrimid-6-one (33.5 g.), m.p. 2l5 219 C.Recrystallisation from ethanol gave pure 4-amino-2-isopropyl-5-phenylazopyrimid 6 one (8.3 g.), m.p. 235-236 C.(with decomposition).

By proceeding in a similar manner, but substituting 4-amino-2-isobutylpyrimid-6-one for the 4-amino-2-isopropylpyrimid-6-oneused as a starting material in the above preparation, there was prepared4-amino-2-isobutyl-S-phenylazopyrimid-6-one, m.p. 261-263 C. (withdecomposition, recrystallised from isopropanol).

The 4-amino-2-isopropylpyrimid-6-one, used as a starting material in theabove preparation, was prepared as follows:

To a stirred solution of sodium (1.15 g.) in dry ethanol (20 ml.) wasadded ethyl cyanoacetate 1.8 ml.) followed after .15 minutes byisobutyramidine' sulphate 2.25 g.). The mixture was refluxed for 20hours, evaporated to dryness, the residue triturated with water (30 ml.)and the pH adjusted to 6 by the addition of hydrochloric acid. Aftercooling to 0 C., 4-amino-2-isopropylpyrimid-6-one (1.7 g.), m.p. 248250C., was filtered off and recrystallised from ethanol to give4-amino-2-isopropylpyrimid-6-one (0.95 g.), m.p. 254 C.

By proceeding in a similar manner, but substituting isovaleramidinehydrochloride for the isobutyramidine sulphate used as a startingmaterial in the above preparation, there was prepared4-amino-Z-isobutylpyrimid- 6-one, m.p. 229-230 C.

The isobutyramidine sulphate and isovaleramidine hydrochloride used asstarting materials in the above preparations were prepared by a methodsimilar to that described by N. Z. Drozdov and A. F. Bekhli, Zhur.Obshch. Khim, 1944, 14, 280.

EXAMPLE 18 Sodium nitrite (6.0 g.) was added to a solution ofconcentrated hydrochloric acid (24 ml.) in water (24 ml.) at 0 C. Thesolution was stirred at 0 C. while 4,5-diamino-2-cyclohexylpyrimid-6-one6.0 g.) was added in portions during 30 minutes. The cooling bath wasremoved, and the mixture was stirred at room temperature for a further 2hours, and then allowed to stand for 4 hours. The solid was filteredoff, washed with water, and recrystallised from a mixture of ethanol andwater to give 8-aza-2-cyclohexylpurin-6-one (3.2 g.), m.p. 239- 241 C.

By proceeding in a similar manner, but substituting 4,5-diamino-2-(1,l-diphenylethyl)pyrimid-6-one for the 4,5-diamino-2-cyclohexylpyrimid-6-one used as a starting material in theabove preparation, there was prepared 8-aza- 2-(l,l-diphenylethyl)purin-6-0ne, m.p. 267.5-269 C. (recrystallised from amixture of dimethylformamide and water).

The 4,5-diamino-2-cyclohexylpyrimid-6-one, used as a starting materialin the above preparation, was prepared as follows:

To water (50 ml.), stirred at 70 C., were added in alternate portions4-amino-2-cyclohexyl-5-nitrosopyrimiddone (25 g.) and sodium dithioniteuntil the blue colour was discharged. The pale yellow solid was filteredoff and washed with water to give 4,5-diamino 2 cyclohexylpyrimid-6-one(19 g.), m.p. 232-238 C. (with decomposition).

By proceeding in a similar manner, but substituting 4- amino-2-(1,1diphenylethyl)-5-nitrosopyrimid-6-one for the4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one used as a starting materialin the above preparation, there was prepared 4,5-diamino 2(1,l-diphenylethyl)pyrimid-6- one, m.p. 218-220 C. (recrystallised froma mixture of dimethylformamide and water).

The 4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

A mixture of 4-amino-2-cyclohexylpyrimid-6-one (18 g.) and water (150ml.) was stirred and heated to 70 C., and treated slowly with sodiumnitrite (8 g.), followed by an excess of glacial acetic acid. Themixture was stirred for a further 1 hour and the blue solid (25 g.)filtered off and used directly for the next stage. A samplerecrystallised from glacial acetic acid gave pure4-arnino-2-cyclohexyl-S-nitrosopyrimid-6-one, m.p. 233-234 C. (withdecomposition).

The 4-arnino-2-cyclohexylpyrimid 6 one, used as a starting material inthe above preparation, was prepared as follows:

To a stirred solution of sodium g.) in dry ethanol 150 ml.) was addedethyl cyanoacetate (12 ml.) followed after 15 minutes by crudecyclohexanecarboxamidine fiuorosulphonate (10 g.). The mixture washeated under reflux for 20 hours, evaporated to half volume, water ml.)was added and the pH adjusted to 6 by the addition of glacial aceticacid. After cooling to 0 C., the solid was filtered off and washed withwater and acetone to give 4-amino-2-cyclohexylpyrimid-6-one 18 g.), m.p.274-276 C. (with decomposition).

The cyclohexanecarboxamidine fluorosulphonate, used as a startingmaterial in the above preparation, was prepared as follows:

To a stirred solution of crude methyl cyclohexanecarboximidatefluorosulphonate (19 g.) in dry ethanol (100 ml.) was added dropwise asaturated solution of ammonia in ethanol (100 ml.). After stirring for afurther hour at 0-10 C., the mixture was left to stand at roomtemperature for 2 days. The mixture was then evaporated to dryness,triturated with ether, and the crude residual cyclohexanecarboxamidinefluorosulphonate (10 g.) used as such in the next stage of theprocedure, the preparation of 4-amino-2-cyclohexylpyrimid-6-one.

The methyl cyclohexanecarboximide fiuorosulphonate, used as a startingmaterial in the above preparation, was prepared as follows:

Methyl fluorosulphonate (9.5 g.) was added to a solution ofcyclohexanecarboxamide (10 g.; prepared as described by H. E. Baumgartenet al. J. Amer. Chem. Soc., 1957, 79, 3145) in dry dichloromethane (100ml.). After standing at room temperature for 3 days the solution wasevaporated to dryness in vacuo. The residue was triturated with drydiethyl ether and the residual gum (19 g.) used as such in the nextstage of the procedure, the preparation of cyclohexanecarboxamidinefiuorosulphonate.

The 4 amino-2-(1,1-diphenylethyl)-5-nitrosopyrimid- 6-one, used as astarting material in the above preparation, was prepared as follows:

A mixture of l,1-diphenylpropionamidine (0.7 g.), ethyla-oximinocyanoacetate (0.44 g.) and sodium methoxide (from 0.29 g.sodium) in dry methanol (6 ml.) was heated under reflux, with stirring,for 6 hours. The mixture was then cooled to 20 C., diluted with water(=10 ml.) and, with vigorous stirring, acidified to pH 6 by the additionof concentrated hydrochloric acid. The resultant solid was filtered offand recrystallised from aqueous acetic acid to give 4-amino 2 (1,1diphenylethyl)-5- nitrosopyrimid-6-one (0.66 g.), m.p. 229 C. (withdecomposition).

The 1,1-diphenylpropionamidine, used as a starting material in the abovepreparation, was prepared as follows:

A stirred suspension of methyl 1,1-diphenylpropionimidatefluorosulphonate (6.2 g.) in dry ethanol (50 ml.) maintained at C. wastreated dropwise with a saturated solution of ammonia in ethanol (15ml.). After stirring for a further 1 hour at 0-10 C., the mixture wasleft to stand at room temperature for 3 days. The mixture was thenevaporated to dryness and the residue mixed with water (25 ml.) andchloroform (20 ml.), cooled to 0 C., and treated dropwise with aqueoussodium hydroxide solution (5 ml.; 50% w./w.). The chloroform layer wasseparated and the aqueous layer extracted with chloroform (3X 5 ml.).The combined chloroform solutions were dried over sodium sulphate andevaporated to dryness. The residue was triturated with petroleum ether(b.p. 4060 C.) and the solid (2.6 g.) filtered oil and recrystallisedseveral times from a mixture of chloroform and petroleum ether (b.p.40-60 C.) to give 1,1-diphenylpropionamidine (1.2 g.), m.p. 154156.5 C.

The methyl 1,1 diphenylpropionimidate fluorosulphonate, used as astarting material in the above preparation, was prepared as follows:

Methyl fluorosulphonate (2.4 g.) was added to a solution of1,1-diphenylpropionamide (4.5 g., prepared as described by C. R. Hauserand D. S. Hoffenberg, J. Org. Chem., 1955, 20, 1448) in drydichloromethane ml.).

After standing at room temperature for 16 hours, the

solid obtained was filtered off and washed with dry di ethyl ether togive methyl 1,l-diphenylpropionimidate fiuorosulphonate (6.55 g.), m.p.158-162 C.

EXAMPLE 19 2-n-Butyl-4,S-diaminopyrimid 6 one (3.0 g.) was dissolved ina hot mixture of concentrated hydrochloric acid ml.) and water (50 ml.).The solution was filtered hot, and the filtrate evaporated to dryness togive a residue which was then dissolved in water (50 ml.). The solutionwas stirred and maintained at a temperature between 0 and 10 C. duringthe slow addition of sodium nitrite (1.86 g.) and for 1 hour thereafter.The mixture was then left to stand at 0 C. overnight and thenconcentrated and the resulting solid (2.95 g.) filtered off andrecrystallised from water (decolourising by means of charcoal) to givethe sodium salt of 2-n-butyl-8-azapurin- 6-one (0.73 g.), which did notmelt below 340 C.

The 2-n-butyl-4,5-diaminopyrimid-6-one, used as a starting material inthe above preparation, was prepared as follows:

4-Amino-2-n-butyl-5-phenylazapyrimid-6-one (5 .6 g.) was dissolved in amixture of ethanol (90 ml.) and water (90 ml.) and the solution heatedalmost to boiling. Sodium dithionite (13.6 g.) was added portionwise atsuch a rate as to maintain reflux, and then the mixture was heated atreflux for a further 1 hour. The mixture was evaporated to dryness, theresidue triturated with icewater (90 ml.) and left to stand at 0 C.overnight. The resultant solid was filtered off and washed withice-water to give 2-n-butyl-4,5-diaminopyrimid-6-one (3.0 g.), m.p.160165 C., sufliciently pure for use in the next stage of thepreparation.

An aliquot was recrystallised from water to give pure2-n-butyl-4,5-diaminopyrimid-6-one, m.p. 169170 C.

The 4-amino-2-n-butyl-5-phenylazopyrimid-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

To a solution of 4-amino-2-n-butylpyrimid-6-one (7.65 g.) and sodiumhydroxide (3.7 g.) in water (115 ml.) was added, at below 5 C., benzenediazonium chloride solution prepared (by the method well known in theart) from aniline (4.64 ml.), and the mixture was then heated to refluxfor 1 hour. The pH was adjusted to 6 by the addition of aqueous sodiumhydroxide solution, the product was filtered off, washed with water,dried and recrystallised from ethanol to give 4amino-2-n-butyl-5-phenylazopyrimid-6-one (2.52 g.), m.p. 266-270 C., pure enough for usein the next stage of the preparation.

An aliquot was recrystallised from ethanol to give pure4-amino-2-n-butyl-S-phenylazopyrimid-6-one, m.p. 273- 274 C.

The liquors were combined and evaporated and the residue (7.2 g.) wasagain dissolved in a solution of sodium hydroxide (3.4 g.) in water (104ml.) and treated with a further quantity of benzene diazonium chloridesolution (prepared from 4.3 g. aniline). By continuing as above, therewas produced a further quantity of 4-amino-2-n-butyl-5-phenylazopyrimid-6-one (5.6 g.), m.p. 265- 270 C.

The 4-amino-2-n-butylpyrimid-6-one, used as a starting material in theabove preparation, was prepared as follows:

Ethyl cyanoacetate (14.7 ml.) was added to a solution of sodium (9.5 g.)in dry ethanol (135 ml.), the mixture was stirred for 1 hour, treatedwith n-valeramidine hydrochloride (18.8 g.,- prepared by the method ofA. P. T. Easson and F. L. Pyman, J. Chem. Soc., 1931, 2991) and heatedto reflux for 3 days. The mixture was evaporated to dryness, the residuetriturated with water ml.) and the solution heated to 60 C., treatedwith glacial acetic acid until pH 6 Was attained, and left to stand at 0C., overnight. The resultant solid was then filtered olf and washed withwater to give 4-amino-2-n-butylpyrimid- 6-one (169 g.), m.p. 242245 C.,pure enough for use in the next stage of the preparation.

An aliquot was recrystallised from ethanol to give pure4-amino-2-n-butylpyrimid-6-one, m.p. 252-253 C.

EXAMPLE 20 A solution of 6-amino-8-aza-2-phenylpurine (0.5 g.) in Nhydrochloric acid (100 ml.) was treated with a solution of sodiumnitrite (0.75 g.) in water (25 m1.) and heated on the steam bath for 3hours. A further quantity of sodium nitrite (0.75 g.) was then added,and heating was continued for a further 12 hours. The resulting solidwas filtered off and recrystallised from aqueous dimethylformamide togive 8-aza-2-phenylpurin-6-one (0.25 g.), m.p. 278280 C. (withdecomposition).

The 6-amino-8-aza-2-phenylpurine, used as a starting inaterial in theabove preparation, was prepared as folows:

Sodium nitrite (6 g.) was dissolved in an ice-cold solution ofconcentrated hydrochloric acid (50 ml.) in water (50 ml.).4,5,6-Triamino-2-phenylpyrimidine (8.8 g.; prepared as described by J.Weinstock, R. Y. Dunoif and J. G. Williams, J. Med. Chem. 1968, 11, 542)was added in portions with stirring. A further quantity of sodiumnitrite (6 g.) was added, and the mixture was stirred at roomtemperature for 3 hours. The solid obtained was filtered off, washedwith water and dissolved in 15% aqueous ammonia. The solution wasfiltered and acidified to pH 6 with glacial acetic acid. The solidobtained was filtered off, washed with water, and recrystallised fromaqueous dimethylformamide, to give 6-amino-8-aza-2- phenylpurine (4 g.),which did not melt below 300 C.

EXAMPLE 21 5-Amino-4-carbamoyl-1H-1,2,3-triazole (2.5 g.; prepared bythe method of J. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956,78, 5832), N-methylbenzamidine hydrochloride (4.2 g.) and anhydroussodium acetate (3.3 g.) were heated together at 200 C. for 3 hours. Themixture was cooled and dissolved in 15% aqueous ammonia 25 ml.). Thesolution was stirred with charcoal, filtered and acidified withconcentrated hydrochloric acid. The solid which separated was filteredoff, washed with water, boiled with ethanol and filtered hot to give8-aZa-2-phenylpurin-6-one (0.12 g.), m.p. 274276 C. (withdecomposition).

EXAMPLE 22 Sodium nitrite (6.8 g.) was dissolved in water (150 ml.) andmixed with 2N aqueous sodium hydroxide solution (54 ml.) and thesolution, simultaneously with a solution of crude 4,5-diamino-2(3-benzylphenyl)pyrimid- 6-one (11.1 g.) in glacial acetic acid (54ml.), Was added with stirring to ice-cooled glacial acetic acid (33 ml.)in such a manner that the temperature remained below 15 C. Stirring wascontinued for a further 1 hour and the mixture was kept at C. overnight.The solid obtained was filtered off, washed with water andrecrystallised from ethanol to give 8-aza-2-(3-benzylphenyl)purin- 6-one(2.1 g.), m.p. 249251 C. (with decomposition).

The crude 4,5-diamino-2-(3-benzylphenyl)pyrimid-6- one, used as astarting material in the above preparation, Was prepared as follows:

4 Amino 2 (3 benzylphenyl) nitrosopyrimid- 6-one (1l.95,g.) wassuspended in water (250 ml.), and triethylamine (20 ml.) was added,giving a purple-red solution. Sodium dithionite (12 g.) was added inportions during 30 minutes with shaking and heating at 60 C. Aftercooling, the mixture was extracted three times with chloroform, and thecombined extracts were dried over magnesium sulphate and evaporated togive crude 4,5-diamino-2-(S-benzylphenyl)pyrimid-6-one (11.1 g.),sufficiently pure to use in the above preparation of 8- aza-2-3-benzylphenyl) purin-6-one.

The 4 amino 2 (3 benzylphenyl) 5 nitrosopyrimid-6-one, used as astarting material in the above preparation, was prepared as follows:

.3-Benzylbenzamidine hydrochloride (12.3 g.) and ethyla-oximinocyanoacetate (7.1 g.) were added to a solution of sodium (4.6g.) in anhydrous ethanol (60 ml.). The mixture was heated under refluxwith stirring for 5 holds and then allowed to stand at room temperatureovernight. The mixture was poured into water (600 ml.), acidified to pH5 with glacial acetic acid and chilled for 3 hours. The solid obtainedWas filtered off and washed with water to give4-amino-2-(3-benzylphenyl)-5-nitrosopyrimid-6-one (11.95 g.), m.p.145-148 C. (with decomposition).

The 3-benzylbenzamidine hydrochloride, used as a starting material inthe above preparation, was prepared as follows:

3-Benzylbenzonitrile (83.45 g.: prepared as described by C. R. Hauser,W. Q. Beard and F. N. Jones, J. Org. Chem., 1961, 26, 4790) wasdissolved in a mixture of anhydrous ethanol (52 ml.) and anhydrouschloroform (390 ml.). The solution was saturated with anhydrous hydrogenchloride at 0 C. and kept at 0 C. for 3 days. The solvent was evaporatedin vacuo and the residue triturated with anhydrous diethyl ether. Thesolid obtained (78 g.) was treated with saturated anhydrous ethanolicammonia (600 ml.), and the mixture maintained at 0 C. for 3 days. Asmall amount of ammonium chloride was filtered off and the filtrate wasevaporated in vacuo. The gummy residue was triturated with anhydrousdiethyl ether to give a solid, which was filtered 01f and extracted withhot water. The extract was filtered and evaporated to dryness in vacuo.The resulting residue was recrystallised from a mixture of ethanol anddiethyl ether (with the aid of charcoal) to give 3-benzylbenzamidinehydrochloride (30.1 g.), m.p. 178-l80 C.

EXAMPLE 23 8-Aza-9-benzyl-2-(2-methoxyethyl)purin-6-one (3.5 g.) wasdissolved in redistilled liquid ammonia (70 ml.). Sodium (0.55 g.) wasadded in portions, with stirring, under reflux. Refluxing was continuedfor a further 30 minutes, the condenser was removed, an excess ofammonium chloride was added, and the ammonia allowed to evaporate. Theresidue was dissolved in water, adjusted to pH 5 with 2N hydrochloricacid and continuously extracted with ethyl acetate overnight. Theextract was discarded. The aqueous layer was adjusted to pH 3 with 2Nhydrochloric acid and again continuously extracted with ethyl acetateovernight. The extract was evaporated in vacuo, to give a residual oilwhich slowly crystallised. The solid obtained was recrystallised from amixture of ethyl acetate and diethyl ether to give8-aza-2-(2-methoxyethy1)purin-6-one (0.6 g.), mp. 128-131" C.

The 8-aza-9-benzyl 2 (2-methoxyethyl)purin-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

5 Arnino-1-benzyl-4-carbamoyl-1,2,3-triazole (2.17 g.) was suspendedwith stirring in 3-methoxypropionyl chloride (5 ml.), cooled in ice, andtreated dropwise with concentrated sulphuric acid (0.7 ml.). The mixturewas stirred overnight, allowing it to attain room temperature, and thenpoured into excess ice-water to give a gum. The product was extractedwith methylene chloride, and the extract was dried over magnesiumsulphate and evaporated to give a yellow gum (2.1 g.). This gum wasdissolved in ethanol (21 ml.), and treated with 2N sodium carbonate (21ml.). The mixture was heated under reflux for 20 hours, evaporated todryness, treated with water (20 ml.), and some insoluble solid removedby filtration. The aqueous alkaline filtrate was acidified to pH 4 withconcentrated hydrochloric acid, and the resulting solid (1.06 g.)filtered off and recrystallised from ethanol to give8-aza-9-benzyl-2-(2-methoxyethyl)purin-6-one (0.71 g.), m.p. 181-183 C.

EXAMPLE 24 A solution of 4,5-diamino-2-(2-ethoxyethyl)pyrimid-6- one(2.57 g.) in a mixture of N hydrochloric acid (12.4 ml.) and water (12.4ml.) was cooled to 0 C. and treated with sodium nitrite (1.4 g.), slowlyin portions, and then stirred at 0 C. overnight. The mixture was thenfiltered to give a solid (a) and a filtrate (b).

The solid (a) [crude 8-aza-2-(2-ethoxyethyl)purin-6- one; 1.4 g.] wasdissolved in dry methanol (15 ml.) and treated with ethylenediamine (2.0ml.). The mixture was warmed for 5 minutes, treated with excess drydiethyl ether ml.) at 0 C., and the resulting gum was triturated withdry diethyl ether to give a solid (1.5 g.). This solid wasrecrystallised from a mixture of dry ethanol (25 ml.) and ethyl acetate(35 ml.) to give the ethylenediamine salt of 8-aza 2(2-ethoxyethyl)purin-6-one (0.66 g.), mp. 191-194 C. (withdecomposition).

The filtrate (b) was brought to pH 5 by means of dilute hydrochloricacid, extracted with ethyl acetate, and the extract dried over magnesiumsulphate and evaporated to dryness to give a further quantity of crude8-aza-2- (Z-ethoxyethyl)purin-6-one (1.4 g.).

The 4,5-diamino-2-(2-ethoxyethyl)pyrimid-6-one, used as a startingmaterial in the above preparation, was prepared as follows:

4-Amino-2-( 2 ethoxyethyl)-5-phenylazopyrimid-6-one (7.7 g.) wasdissolved in hot ethanol ml.), and water (125 ml.) was added. Themixture was heated almost to boiling, then sodium dithionite (19.2 g.)was added at such a rate as to maintain gentle refluxing. The mixturewas then heated under reflux for a further 30 minutes, treated with anadditional quantity of sodium dithionite (5 g.), again heated under thereflux for 30 minutes, and then evaporated to dryness. The residue wasdissolved in water ml.) and continuously extracted with ethyl acetatefor 20 hours. The ethyl acetate extract was dried over magnesiumsulphate, and evaporated to give crude 4,5-diamino 2(2-ethoxyethyl)pyrimid-6- one (2.7 g.), sufiiciently pure for use in thenext stage.

The 4 amino-2- (Z-ethoxyethyl)-5-phenylazopyrimid-6- one, used as astarting material in the above preparation, was prepared as follows:

4Amino-2-(2-ethoxyethyl)pyrimid-6-one (1.68 g.) was dissolved in astirred solution of sodium hydroxide (0.8 g.) in water (25 ml.),maintained at below 5 C., and treated dropwise with a solution ofbenzene diazonium chloride prepared (by the method well known in theart) from aniline (1.0 ml.) in a mixture of concentrated hydrochloricacid (2.75 ml.) and water (2.75 ml.).

The orange mixture was then stirred at 2 C. for 3 hours, filtered, andthe orange solid washed with ice-water, dried and recrystallised fromaqueous ethanol to give 4- amino-Z-(Z ethoxyethyl)-5-phenylazopyrimid 6one (0.7 g.), m.p. 205 C. (with decomposition).

The 4-amino-2-(2-ethoxyethyl)pyrimid-6-one, used as starting material inthe above preparation, was prepared as follows:

To a solution of sodium ethoxide in ethanol, prepared from sodium (47.5g.) and dry ethanol (675 ml.), was added, slowly with cooling andstirring, ethyl cyanoacetate (74 ml.), followed by a solution of3-methoxypropionamidine hydrochloride (96 g.) in dry ethanol (173 ml.).The mixture was stirred and heated under reflux for 40 hours, evaporatedto dryness in vacuo, the residue triturated with water (67.5 ml.),acidified to pH 6 with concentrated hydrochloric acid, left to stand at0 C. overnight and filtered. The aqueous filtrate was extractedcontinuously with ethyl acetate for 3 days and the extract dried andevaporated to dryness to give crude4-amino-2-(2-ethoxyethyl)pyrimid-6-one (11.38 g.), m.p. 167-170 C.,sufficiently pure for use in the next stage. A sample was purified bychromatography on silica gel, followed by recrystallisation fromethanol, to give pure 4-am1no-2- (Z-ethoxyethyl)pyrimid-6-one, m.p.19l-194 C.

It is to be noted that exchange of the methoxy group for an ethoxy groupwith the ethanol solvent occurred in the presence of the sodiumethoxide.

The 3-methoxypropionamide hydrochloride, used as a starting material inthe above preparation, was prepared as follows:

3-Methoxypropionitrile (prepared as described by I. H. McGregor and C.Pugh, J. Chem. Soc., 1945, 535) (99 g.) was dissolved in a mixture ofdry methanol (40.5 ml.) and dry diethyl ether (50 ml.) and treated at 0C. with hydrogen chloride gas until 39.3 g. was absorbed (1.25 hours).The flask was stoppered securely and left to stand at 0 C. for 4 days,the hygroscopic solid which separated was filtered off, washed with drydiethyl ether and dried in vacuo. The imino ether hydrochloride thusobtained was treated with an ice-cold saturated dry cthanolic ammoniasolution (400 ml.) and left to stand at 0 C. for 4 days, and thenstirred for 20 hours at room temperature. The mixture was evaporated todryness, the residue heated under reflux with dry ethanol (200 ml.),filtered, and evaporated to give crude 3-methoxypropionamidehydrochloride (109 g.), pure enough for use, without furtherpreparation, in the next stage. The product was characterised byconversion to the picrate, m.p. 169-171 C.

EXAMPLE 25 m.p. 266 C. (with decomposition).

The 8-aza-9-benzyl-2-phenylpurin-6-one, used as a starting material inthe above preparation, was prepared by any of the following methods:

(a) 5 Benzamido 1 benzyl-4-carbamoyl-1,2,3-triazole (1.0 g.), saturatedaqueous sodium bicarbonate solution (5 ml.) and ethanol (5 ml.) wererefluxed together for 29 hours. The mixture was cooled in ice, acidifiedwith 2N sulphuric acid and stirred at 0 C. for 20 minutes. The solid wasfiltered off, washed with water and boiled with ethanol to give8-aza-9-benzyl-2-phenylpurin-6-one (0.45 g.), m.p. 270271 C.

The 5 benzamido l benzyl-4-carbamoyl-1,2,3-triazole, used as a startingmaterial in the above preparation, was prepared as follows:

1 Benzyl-4-carbamoyl-5-formamido-l,2,3-triazole (40 g.; prepared asdescribed by A. Albert, J. Chem. Soc., 1969 (C), 152) was dissolved in2N sodium hydroxide solution (156 ml.), and treated with alternatesuccessive portions of benzoyl chloride total (24 ml.) and 2N aqueous,sodium hydroxide solution (total 140 ml.) with vigorous agitation, andcooling with ice, over a period of 2 hours. The solution was thenacidified to pH 4 with concentrated hydrochloric acid, again coolingwith ice, and the precipitated solid was filtered ofi, dissolved in 2Nsodium hydroxide solution (208 ml.) and the solution stirred at 0 C.while portions of benzoyl chloride (total 57 ml.) and 2N sodiumhydroxide solution (total 331 ml.) were added alternately over minutes.The resultant mixture was stirred for a further minutes at 0 C. beforebeing acidified to pH 4 with concentrated hydrochloric acid, thetemperature being maintained at 0 C. The solid was filtered off andwashed successively with water, diethyl ether and water. The solidproduct was dried, and recrystallised from ethanol to giveS-benzamido-l-benzyl- 4-carbamoyl-1,2,3-triazole (23.1 g.), m.p. 191l92C.

(b) 5 Benzamido 4 benzoylcarbamoyl-l-benzyl- 1,2,3-triazole (1 g.), 2Naqueous sodium carbonate solution (5 ml.) and ethanol (5 ml.) wererefluxed together for 20 hours. The mixture was cooled in ice, acidifiedwith 2N hydrochloric acid and stirred at 0 C. for 20 minutes. The solidwas filtered off, washed with water and dissolved in the minimumquantity of warm dimethylformamide. The solution was filtered, dilutedwith ethanol and cooled to 0 C. The resulting solid was filtered to give8-aza-9-benzyl-2-phenylpurin-6-one (0.15 g.), m.p. 274276 C. (withdecomposition).

The 5 benzamido 4 benzoylcarbamoyl-l-benzyl- 1,2,3-triazole, used as astarting material in the above preparation, was prepared as follows:

Concentrated sulphuric acid (1.5 ml.) was added dropwise, underanhydrous conditions, to an ice-cooled, stirred suspension ofS-amino-1-benZyl-4-carbamoyl- 1,2,3-triazole (2.17 g.; prepared asdescribed by J. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956,78, 5832) in benzoyl chloride (24 ml.). Stirring was continued at roomtemperature overnight. The clear solution which formed was then pouredinto ice-water, the precipitated solid was filtered off, washed wellwith water and diethyl ether to give5-benzamido-4-benzoylcarbamoyl-l-benZyl-1,2,3-triazole (1.8 g.), m.p.171173 C., suitable for use in the next stage of the preparation. Analiquot was recrystallised from ethanol to give pure5-benzamido-4-benzoylcarbamoyl l benzyl 1,2,3 triazole, m.p. 182-186 C.

(c) Benzoyl chloride (34.8 ml.) was added dropwise, under anhydrousconditions, to an ice-cooled, stirred suspension of 5 amino 1benzyl-4-carbamoyl-1,2,3-triazole (32.55 g.; prepared by the method ofJ. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956, 78, 5832) inanhydrous pyridine (225 ml.). The mixture was then stirred at roomtemperature for 40 hours, filtered, and poured into a large volume ofcold water. The gummy precipitate solidified on standing, and wasfiltered off, and washed well with water, giving a mixture of monoauddi-benzoyl derivatives of 5-amino-1-benzyl-4-carbamoyl-1,2,3-triazole(56 g.).

